REVIEW
Post-transplantation Outcomes in Patients with PAor MMA: A Review of the Literature
Sufin Yap . Roshni Vara . Ana Morais
Received: February 4, 2020 / Published online: April 8, 2020� The Author(s) 2020
ABSTRACT
Introduction: Liver transplantation is recog-nised as a treatment option for patients withpropionic acidemia (PA) and those withmethylmalonic acidemia (MMA) without renalimpairment. In patients with MMA and mod-erate-to-severe renal impairment, combinedliver–kidney transplantation is indicated. How-ever, clinical experience of these transplanta-tion options in patients with PA and MMAremains limited and fragmented. We undertookan overview of post-transplantation outcomesin patients with PA and MMA using the currentavailable evidence.Methods: A literature search identified publi-cations on the use of transplantation in patientswith PA and MMA. Publications were consid-ered if they presented adequate demographicand outcome data from patients with PA or
MMA. Publications that did not report anyspecific outcomes for patients or providedinsufficient data were excluded.Results: Seventy publications were identified ofwhich 38 were full papers. A total of 373patients underwent liver/kidney/combinedliver–kidney transplantation for PA or MMA.The most typical reason for transplantation wasrecurrent metabolic decompensation. A total of27 post-transplant deaths were reported inpatients with PA [14.0% (27/194)]. For patientswith MMA, 18 post-transplant deaths werereported [11% (18/167)]. A total of 62 compli-cations were reported in 115 patients with PA(54%) with cardiomyopathy (n = 12), hepaticarterial thrombosis (HAT; n = 14) and viralinfections (n = 12) being the most commonlyreported. A total of 52 complications werereported in 106 patients with MMA (49%) withviral infections (n = 14) and renal failure/im-pairment (n = 10) being the most commonlyreported.Conclusions: Liver transplantation and com-bined liver–kidney transplantation appears tobenefit some patients with PA or MMA, respec-tively, but this approach does not providecomplete correction of the metabolic defect andsome patients remain at risk from disease-re-lated and transplantation-related complica-tions, including death. Thus, all treatmentavenues should be exhausted before considera-tion of organ transplantation and the benefitsof this approach must be weighed against the
Digital features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.11994477.
S. Yap (&)Department of Inherited Metabolic Diseases,Sheffield Children’s Hospital, Sheffield, UKe-mail: [email protected]
R. VaraEvelina London Children’s Hospital, London, UK
A. MoraisChild Nutrition and Metabolic Diseases Unit,University Hospital La Paz, Madrid, Spain
Adv Ther (2020) 37:1866–1896
https://doi.org/10.1007/s12325-020-01305-1
risk of perioperative complications on an indi-vidual basis.
Keywords: Kidney transplantation; Livertransplantation; Methylmalonic acidemia;Morbidity; Mortality; Propionic acidemia
Key Summary Points
A literature review was performed toascertain the outcomes associated withliver and or kidney transplantation inpatients with propionic acidemia (PA) ormethylmalonic acidemia (MMA).
Thirty-eight papers and 32 abstracts wereidentified, totalling 373 patients.
Transplantation improved outcome insome patients with PA and MMA, but wasalso associated with appreciable mortality(14% PA, 11% MMA) and complicationsincluding cardiomyopathy, hepaticarterial thrombosis, renal failure/impairment, and viral infections.
While transplantation appears to be ofsome benefit in a subset of patients withPA/MMA, this approach does not providea metabolic cure and patients remain atrisk from disease-related andtransplantation-related complications.
All treatment avenues should ideally beexhausted for PA/MMA before selectingtransplantation.
INTRODUCTION
Propionic acidemia (PA) and methylmalonicacidemia (MMA) are rare inborn errors ofmetabolism presenting in infancy with episodesof metabolic acidosis that can lead to earlymortality and significant morbidity [1–3]. BothPA and MMA are characterised by the accumu-lation of propionic acid and/or methylmalonicacid in plasma, urine, and other body fluids, due
to defects in the enzymes propionyl-CoA car-boxylase and methylmalonyl-CoA mutase,respectively.
Patients with PA and/or MMA typically pre-sent shortly after birth with acute deterioration,metabolic acidosis, and hyperammonaemialeading to either severe intellectual disabilitiesor death [1]. For these patients with ‘classical’PA and MMA, dietary restriction (a low-protein,high-energy diet) together with oral medication(typically carnitine) has remained the coretherapy for decades. However, despite intensivemedical efforts, frequent episodes of metabolicdecompensation occur with inevitable compli-cations [1].
Solid-organ transplantation, such as singleliver or kidney transplantation, or combinedliver–kidney transplantation, has become aneffective alternative treatment for metabolicdisease in recent decades [1]. The role of liver,kidney, or combined liver–kidney transplanta-tion in patients with PA/MMA is currentlyevolving and, while not considered ‘curative’, istypically undertaken as an ‘enzyme replace-ment therapy’ [4]. However, any decision tocarry out a transplantation is a complicated onewhich requires a comprehensive understandingof the underlying disease, the risks and benefitsof transplantation, and current therapeuticalternatives [5]. Furthermore, clinical experi-ence of transplantation in PA and MMA remainsboth limited and fragmented due to the lowprevalence of these diseases [4, 6].
The purpose of this review is to provide anoverview of post-transplantation outcomes inpatients with PA and MMA.
METHODS
A literature search was undertaken on 10 April2019 to identify suitable papers for inclusion inthe present review. The literature search toolsused were PubMed, Embase and Biosys. Thesearch string was [(propionic OR methyl-malonic) AND acidemia*] AND [(transplant ORtransplantation) AND aciduria*]. No date limi-tations were applied. Suitable references forinclusion included abstracts and full papers,clinical studies, case studies, and retrospective
Adv Ther (2020) 37:1866–1896 1867
analyses of patients with PA and/or MMA. Anyreferences which included patients with PA orMMA as part of a pooled population of patientswith inherited metabolic disorders but did notreport any specific outcomes for these patientswere excluded, as were abstracts providinginsufficient data. Given the methodology used,this review was undertaken to assess any trendsarising from the use of liver/kidney/combinedliver–kidney transplantation in patients withPA/MMA.
This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.
RESULTS
Patient Demographics and Follow-up
Seventy suitable references (retrospective anal-yses and case studies) were identified, 32 ofwhich were meeting abstracts. A summary oftransplantation type and median patient agetaken from these references is shown in Table 1.A total of 195 and 167 patients underwent liver/kidney/combined liver–kidney transplantationfor PA and MMA, respectively (a total of 373
transplantations). In addition, a total of nineand two retransplantations were required inpatients with PA and MMA, respectively. Singleorgan liver transplantation was performed morecommonly in both PA and MMA (total n = 307,PA n = 193; MMA n = 114), when comparedwith kidney (PA n = 2; MMA n = 21) or com-bined liver–kidney transplantation (PA n = 0;MMA n = 32) (retransplantations not included).Median age at transplantation ranged from 0.25to 42 years in patients with PA and from 0.4 to28.0 years in patients with MMA. The mosttypical reason for any type of transplantation inpatients with PA and MMA was recurrentmetabolic decompensation. Follow-up data toshow outcomes by type of transplantation wereavailable for all PA (n = 195; available follow-uprange 0–22 years) and MMA (n = 167; range0.04–16 years) patients, although specific tim-ings of follow-up were not always provided.
Of the 70 references identified, 38 were fullpapers which contained sufficient patientinformation, both pre-operatively and post-transplantation, along with a suitable follow-upduration to enable a more detailed overview. Asummary of key findings from these referencesis shown in Tables 2 and 3. Available data fromthe identified abstracts were limited and aresummarised in the ‘‘Appendix’’.
Table 1 Overall characteristics of reviewed patients
Characteristic PA MMA
Liver transplantation 193 114
Kidney transplantation 2a 21
Combined transplantation 0 32
Retransplantation 9 2
Total transplantation 204 169
Median age at transplant, range, yearsb 0.25–42.0 0.4–28.0
Mortality 27/195 (14%) 18/167 (11%)
Complicationsc 62/115 (54%) 52/106 (49%)
MMA methylmalonic acidemia, PA propionic acidemiaa One patient had a liver transplantation followed approximately 3 years later by a kidney transplant [7]b Based on available datac Publications not reporting complications and their associated patient numbers were excluded
1868 Adv Ther (2020) 37:1866–1896
Table2
Overviewof
data
from
publishedpapersof
PAstudies/case
studies
References
nTransplant
type
a
Median
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
of
follo
w-up
Deaths(cause
and
number)
Arrizza
etal.
[8]
1OLT
22(n/a)
No de
compensations
Reversalof
severe
cardiomyopathy
(n=1)
Nonereported
10(n/a)
Nonereported
Barshes
etal.
[9]
2OLT
1.7(1.3–2
.0)
No de
compensations
Improvem
entin
bilateralganglia
lesions(n
=1)
Improved
cognition
(n=1)
HAT
requiringretransplant
(n=1)
1.4(0.3–2
.4)
Nonereported
Charbit-
Henrion
etal.[10]
12LT
3.2(1.6–6
.8)
No de
compensations
Reversalof
cardiomyopathy
(n=3)
Repeattransplantationrequired
(n=4):
biliary
cirrhosissecond
aryto
HAT
(n=2),p
rimarynon-function
ofthe
graft(n
=1),h
epaticdysfun
ctionafter
HAT
(n=1)
Moderaterenalfailure
(n=1)
PTLD
(n=2)
Bipolar
disorder
(n=1)
Kidneytransplant
(n=1)
Chronichepatitis(n
=1)
Biliarycirrhosis(n
=2)
Biliarystricture(n
=1aftersecond
transplant)
ARDS(n
=4)
Acute
encephalopathy
(n=1)
Biliarysepsis(n
=1)
17(0–2
1)Multi-organ
failure
(n=4)
Hepaticfailure
(n=3)
Adv Ther (2020) 37:1866–1896 1869
Table2
continued
References
nTransplant
type
a
Median
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
of
follo
w-up
Deaths(cause
and
number)
Critelli
etal.
[11]
3LDLT
8.7 (1
.2–1
1.8)
No de
compensations
Not
reported
HAT
(n=1)
CMVinfection(n
=1)
Colonicperforation(n
=1)
EBVviremia(n
=2)
2.1(1.6–2
.1)
Nonereported
Kasahara
etal.[12]
3LDLT
2(0.6–2
.2)
No de
compensations
Normalmental
developm
ent(n
=3)
CMVinfection(n
=2)
Intestinalperforationwhich
necessitated
relaparotomy(n
=1)
3.3(n/s)
Nonereported
Kasahara
etal.[13]
9LDLT
2.2 (0
.4–1
2.0)
Recurrent
metabolic
decompensation
(n=9)
Noepisodes
ofcardiac
insufficiency
reported
Septiccomplications
(n=4)
Not reported
Sepsis(n
=4)
Kayleret
al.
[14]
1LT
3(n/a)
Not
specified
Not
specified
Not
specified
0.25
(n/a)
Cause
notspecified
(n=1)
Lam
etal.
[15]
1KT
42(n/a)
n/s
n/s
n/s
3(n/a)
Nonereported
Moguilevitch
and
Delphin
[16]
1LT
1(n/a)
Not
reported
Not
reported
Increase
inliver
function
tests(n
=1)
n/s
Nonereported
Morioka
etal.
[17]
3LDLT
2(1–5
)No de
compensations
Not
reported
Nonereported
2.5(1.8–4
.9)
Nonereported
Nagao
etal.
[18]
1LDLT
0.6(n/a)
No de
compensations
Improved
neurologic
function
(n=1)
Intestinalperforation(n
=1)
CMVinfection(n
=1)
18(n/a)
Nonereported
1870 Adv Ther (2020) 37:1866–1896
Table2
continued
References
nTransplant
type
a
Median
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
of
follo
w-up
Deaths(cause
and
number)
Quintero
etal.[19]
6LDLT
5.2(1.3–7
.5)
No de
compensations
Stabilisation/
improvem
entof
baselin
eneurological
impairment(n
=6)
HAT
(n=2)
Arterialvasospasm
without
thrombus
during
surgery(n
=2)
Delayed
biliary
anastomosis(n
=2)
1.5(0.5–4
.0)
Nonereported
Ram
mohan
etal.[20]
6APO
LT
(n=5)
OLT
(n=1)
n/s
n/s
Stabilisation
of
cardiomyopathy
(n=1)
HAT
(n=1;
APO
LT)
Graftdysfun
ctionleadingto
severe
metabolicdecompensation(n
=1;OLT)
4.2(n/s)
Severe
metabolic
decompensation
(n=1)
Relaet
al.
[21]
1ALT
2(n/a)
Metabolic
decompensation
(n=1)
Acceptableneurological
developm
ent(n
=1)
Nonereported
10(n/a)
Nonereported
Rom
anoetal.
[22]
2OLT
N/a
No de
compensations
Reversalof
cardiomyopathy
(n=2)
Cardiac
arrest(recovered)(n
=1)
14.5 (7.0–2
2.0)
Nonereported
Schlenzig
etal.[23]
2OLT
8.0(7.0–9
.0)
No de
compensations
Neurologicalsequelae
involvingbasalganglia
(n=1)
Acute
rejection(n
=1)
Chronicrejection(n
=1)
CMVinfection(n
=2)
IncompleteHAT
(n=1)
Persistent
insulin
-dependent
diabetes
mellitus
(n=1)
1.3(n/s)
IncompleteHAT
(n=1)
Shanmugam
etal.[24]
5APO
LT2.75 (0
.7–4
.6)
No de
compensations
Progressive
improvem
entin
developm
entalscores
(n=5)
HAT
(n=1)
Higham
moniawithout
encephalopathy
(n=1)
Acute
cellularrejection(n
=4)
2.7(1.6–4
.2)
Nonereported
Adv Ther (2020) 37:1866–1896 1871
Table2
continued
References
nTransplant
type
a
Median
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
of
follo
w-up
Deaths(cause
and
number)
Varaet
al.
[25]
5LT
1.5(0.8–7
.0)
No de
compensations
Neurological
decompensation
(n=1)
HAT
requiringretransplantation(n
=1)
Metabolicstroke
(n=1)
7.3 (2
.2–1
5.0)
Nonereported
Yorifu
jiet
al.
[26]
3LDLT
2(1.2–5
.1)
Reduced
metabolic
decompensation
Improvem
entin
neurologicalhealth
(n=1)
Datan/aforother
patients
Acute
metabolicdecompensation(n
=1)
1.4(0.7–3
.8)
Nonereported
ALTauxiliary
liver
transplantation,
APO
LTauxiliary
partialorthotopicliver
transplantation,
ARDSacuterespiratorydistresssynd
rome,CMVcytomegalovirus,E
BVEpstein–B
arr
virus,HAThepaticartery
thrombosis,KTkidn
eytransplantation,
LDLTliving-donorliver
transplantation,
LTliver
transplantation,
OLTorthotopicliver
transplantation,
PTLD
post-transplantlymphoproliferativedisease,n/anotavailable,n/snotspecified
aVarious
typesof
liver
transplantationused
1872 Adv Ther (2020) 37:1866–1896
Table3
Overviewof
data
from
publishedpapersof
MMA
studies/case
studies
References
nTransplant
type
aMedian
(range)
transplant
ageyears)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
Deaths(cause
andnu
mber)
Brassier
etal.
[27]
4KT
7.9(5–1
0.2)
No decompensations
Neurologicalstability
(n=2)
Hepatoblastom
afollowed
by
neurologicalcomplications
(n=1)
Acuterejectionresponsive
to
prednisone
(n=1)
Movem
entdisorder
(n=1)
2.8(1.8–4
.6)
Hepatoblastom
a
followed
by
neurological
complications
(n=1)
Chenet
al.
[28]
4LT
1.4 (0.7–2
.1)
0.08
peryear
Continu
eddevelopm
ent
(n=4)
Nonereported
3.5(0.2–7
.7)
Nonereported
Clothier
etal.
[29]
1KT
12(n/a)
No decompensations
Not
reported
Mild
focalinterstitialfi
brosis
(n=1)
6(n/a)
Nonereported
Critelli
etal.
[11]
6OLT (n=1)
Com
bined
LT/K
T
(n=5)
8.4(1.9
–21.6)
No decompensations
Not
reported
Near-completestenosisof
therighthepaticvein
atits
junction
withtheinferior
vena
cava
(n=1)
HAT
(n=1)
Renalrejection(n
=1)
Biliaryanastomoticstricture
(n=1)
EBVviremia(n
=1)
Mild
tubulointerstitialinjury
(n=1)
3.4(1–1
1.6)
Nonereported
Adv Ther (2020) 37:1866–1896 1873
Table3
continued
References
nTransplant
type
aMedian
(range)
transplant
ageyears)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
Deaths(cause
andnu
mber)
Duclaux-
Loras
etal.
[30]
1Com
bined
LT/K
T
10.4
(n/a)
No decompensations
Not
reported
Renalarterialthrombosis
(n=1)
10(n/a)
Nonereported
Hirotsu
etal.
[31]
1LDLT
1.8(n/a)
No decompensations
Not
reported
Nonereported
0.2(n/a)
Nonereported
Kasahara
etal.
[13]
20LDLT
2.2(0.4–1
2)Recurrent
metabolic
decompensation
(n=20)
Not
reported
Progressiverenal
insufficiency
(n=4)
New
onsetof
seizures
(n=3)
Not
specified
Nonereported
Kayler
etal.
[14]
2LT
(n=1)
Com
bined
LT/K
T
(n=1)
14.5 (13–
16)
Not
specified
Not
specified
Liver
retransplantation
(n=1)
EBVviremia(n
=1)
PotentialPT
LD
(n=1)
2.5(1.1–3
.9)
Nonereported
Khann
a
etal.
[32]
1Cadaveric
LT
28(n/a)
No decompensations
Not
reported
Nonereported
[1(n/a)
Nonereported
Lubrano
etal.
[33,
34]
1KT
17(n/a)
No decompensations
Not
reported
Chronicallograft
nephropathy(n
=1)
10(n/a)
Nonereported
1874 Adv Ther (2020) 37:1866–1896
Table3
continued
References
nTransplant
type
aMedian
(range)
transplant
ageyears)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
Deaths(cause
andnu
mber)
McG
uire
etal.
[35]
1LT/K
T5(n/a)
One
metabolic
decompensation
at10
months
post
transplantation
Neurological
deterioration
(hem
iplegia,trun
cal
ataxiaandspeech
dyspraxia)
(n=1)
Cerebellarstroke
(n=1)
C10
months
(n/a)
Nonereported
Morioka
etal.
[17]
2LDLT
6.5(1–1
2)Metabolicstroke
(n=1)
Not
reported
Metabolicstroke
(n=1)
Aspergillosis(n
=1)
0.1 (0.04–
0.17)
Metabolicstroke
(n=1)
Aspergillosis
(n=1)
Morioka
etal.
[36]
7LDLT
4.3 (0.6–7
.5)
Metabolicacidosis
(n=2)
Cognitive
deficit
improved
(n=7)
Sepsis(n
=1)
Graftdysfun
ction(n
=1)
CMVviremia(n
=2)
EBVviremia(n
=1)
0.9(0.3–1
.75)
Sepsis(n
=1)
Nagarajan
etal.
[37]
2LT/K
T15.5 (10–
21)
No decompensations
Mentalstatus
changes
(n=1)
Tremors(n
=1)
Mild
reversibleacute
rejectionof
theliver
(n=1)
CMVgastritis(n
=1)
Mentalstatus
changes
(n=1)
Tremors(n
=1)
Mild
glucoseintolerance
(n=1)
3.3(1.5–5
)Nonereported
Adv Ther (2020) 37:1866–1896 1875
Table3
continued
References
nTransplant
type
aMedian
(range)
transplant
ageyears)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
Deaths(cause
andnu
mber)
Niemi
etal.
[38]
14LT
(n=6)
Com
bined
LT/K
T
(n=8)
7.4 (0.8–2
0.7)
No decompensations
Allpatientsmaintained
orim
proved
neurologicalhealth
HAT
requiringliver
retransplantation(n
=1)
Bleedingrequiringre-
exploration(n
=2)
Drainageof
subphrenic
abscess(n
=1),
Seizure(n
=1)
Diabetesmellitus
(n=1)
3.25 (0.25–
14)b
Nonereported
Nyhan
etal.
[39]
1OLT
22(n/a)
No decompensations
Neurologic
manifestations
(n=1)
Progressionof
pre-surgery
renalfailure
(n=1)
Neurologicmanifestations
(n=1)
2(n/a)
Nonereported
Sakamoto
etal.
[40]
13LDLT
9(0.7–7
)Severalmetabolic
episodes
(n=3)
Normalgrow
threported
Severe
adhesive
intestinal
obstruction(n
=1)
Strangulationileus
(n=1)
Bile
duct
stenosis(n
=2)
Acute
renalfailure
(n=1)
Convulsion
(n=2)
Portalvein
stenosis(n
=1)
Sepsis(n
=1)
Cholangitis(n
=2)
8.1(4–1
6)Nonereported
1876 Adv Ther (2020) 37:1866–1896
Table3
continued
References
nTransplant
type
aMedian
(range)
transplant
ageyears)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
Deaths(cause
andnu
mber)
Spadaetal.
[41]
2WholeLT
(n=1)
Split
LT
(n=1)
1.9(0.75–
3)No decompensations
Adequateneurological
developm
ent(n
=2)
Nonereported
7(2–1
2)Nonereported
Stevenson
etal.
[42]
3Com
bined
LT/K
T
10.8
(n/s)
No decompensations
Not
reported
Decreased
renalfunction
(n=1)
[1(n/s)
Nonereported
CMVcytomegalovirus,EBVEpstein-Barrvirus,HAT
hepaticartery
thrombosis,KT
kidn
eytransplantation,
LDLT
living-donorliver
transplantation,
LT
liver
transplantation,LT/K
Tliver/kidneytransplantation,OLTorthotopiclivertransplantation,PT
LDpost-transplantlymphoproliferativedisease,n/anotavailable,n/s
notspecified
aVarious
typesof
liver
transplantationused
bMean(range)transplant
ageshow
n
Adv Ther (2020) 37:1866–1896 1877
Mortality
A total of 27 post-transplant deaths werereported in patients with PA, which equated toa mortality rate of 14.0% (27/194). For patientswith MMA, 18 post-transplant deaths werereported, which equated to a mortality rate of11% (18/167). Causes of death for PA and MMAare presented in Tables 2 and 3, respectively.
PAA retrospective analysis of 12 patients with PAwho underwent liver transplantation reportedthat while the graft survival rate was 60% at5 years, seven of the 12 patients (58%) diedwithin the first year after transplantation (mul-ti-organ failure, n = 4; hepatic failure, n = 3)[10]. Infection is reported as a major cause ofpost-transplant deaths in patients with PA:Kasahara et al. [13] reported that liver trans-plantation in nine patients with PA resulted infour sepsis-related deaths, equating to a mor-tality rate of 44%. However, some studies sug-gest that transplantation appears to be less of arisk in some patients with PA. For example, arecent retrospective analysis of liver transplan-tation by Shanmugam et al. [24] reported sur-vival in patients with PA to be 100% at a medianfollow-up of 32 months. It appears that survivalfollowing transplantation in patients with PAseems to be improving with greater experienceof the procedure. Indeed, the expertise andexperience of the surgical team is an importantprognostic factor for general paediatric livertransplantation [43–46].
MMAPatient mortality following transplantation wasless frequently reported in patients with MMAcompared with patients with PA, with moststudies reporting 100% patient survival. How-ever, three studies identified a post-transplan-tation mortality risk in patients with MMA. Forkidney transplantation, Brassier et al. [27]reported four patients with MMA [mediantransplantation age 7.9 years (range 5–10.2 years)] who received a kidney graft fol-
lowing repeated metabolic decompensations,with progression to chronic kidney disease(CKD) in three of these patients (end-stagekidney disease in two patients and CKD stage IIIin one patient; normal renal function in onepatient) prior to transplantation. One patientdeveloped a hepatoblastoma at the age of 11(less than 2 years post-surgery), followed byneurological complications and death. Thethree other patients remained alive, with twoachieving neurological stability. Morioka et al.[17] reported on two patients with MMA whoboth died after receiving a liver transplantation,equating to a 100% mortality rate; these deathswere caused by metabolic stroke andaspergillosis. One death caused by a metaboliccrisis was identified in a patient with MMAfollowing combined liver–kidney transplanta-tion [47].
Complications
A total of 62 complications (various types) werereported in 115 patients with PA. This equatesto an approximate complication rate of 54%given that some patients experienced morethan one complication. Cardiomyopathy(n = 12), hepatic arterial thrombosis (HAT;n = 14) and viral infections (n = 12) were mostcommonly reported complications amongpatients with PA. A total of 52 complicationswere reported in 106 patients with MMA. Thisequates to an approximate complication rate of49% given that some patients experienced morethan one complication. Viral infections (n = 14)and renal failure/impairment (n = 10) weremost commonly reported complications amongpatients with MMA. Of note, the definition ofwhat constituted a ‘complication’ varied widelybetween publications. Post-transplant compli-cations for patients with PA and MMA are pre-sented in Tables 2 and 3, respectively.
PAComplications related to the transplant proce-dure along with subsequent post-surgery infec-tion appeared to be most commonly reported in
1878 Adv Ther (2020) 37:1866–1896
patients with PA (Table 2). A retrospective studyreported that out of 17 liver transplantationprocedures in 12 patients with PA, HAT wasreported in a total of six transplants (equatingto a 35% risk of HAT), and occurred in succes-sive grafts in two patients [10]. Similarly, Critelliet al. [11] reported that two of three patientswith PA who received a liver transplant devel-oped a recurrent left HAT (equating to a 66%chance of HAT), one that required Fogartycatheter thrombectomy and one that did notresolve despite placement of an aortic conduitgraft, resulting in an associated hepatic allograftinfarction. The same study noted that onepatient developed cytomegalovirus (CMV) vir-emia, while a similar retrospective review ofchildren with PA noted that two of threepatients developed CMV infection followingliver transplantation [12]; all episodes of CMVinfection were successfully treated with intra-venously administered ganciclovir.
MMAPost-transplantation complications variedamongst patients with MMA, although moststudies reported at least one complication(Table 3). Complications following combinedliver/kidney transplantation included renalartery thrombosis (Duclaux-Loras et al. [30])and cerebellar stroke [35]. For liver transplan-tation, complications such as infection (sepsis,CMV and Epstein-Barr virus [EBV]) [36] andHAT [11, 38] were reported. Complications fol-lowing kidney transplantation included hepa-toblastoma [27] and chronic allograftnephropathy [33].
Post-transplant Metabolic Episodes
PAIn the literature available for patients with PA,reports of metabolic episodes ranged from 0% to100% following liver transplantation (Table 2).A retrospective analysis of 12 patients with PAreported no further episodes of acute metabolicdecompensation following liver transplantationeven with a less restricted dietary protein intake
[10]. Similarly, Shanmugam et al. [24] reportedthat of five children with PA and a median ofeight episodes of decompensation per year priorto transplantation, no episodes of metabolicdecompensation occurred either intraopera-tively or immediately after transplantationwhen receiving a protein-unrestricted diet. Incontrast, Kasahara et al. [13] reported that fol-lowing liver transplantation in Japanesepatients with PA/MMA, recurrent metabolicdecompensation was observed in 100% ofpatients despite the administration of proteinrestriction with medications (cobalamin, car-nitine supplementation, and antibiotics toeradicate gut flora). Thus, post-transplant med-ication for the original liver disease had to becontinued in all patients.
MMAIn the literature available for patients withMMA, episodes of metabolic decompensationvaried by transplantation type (Table 3). Forpatients with MMA, the risk of further episodesof metabolic decompensation appeared to behigher following liver transplantation com-pared with kidney or combined kidney/livertransplantation. Kasahara et al. [13] reportedrecurrent metabolic decompensation in 100%of patients with MMA following liver trans-plantation despite the administration of proteinrestriction with medications, leading to thecontinuation of pre-surgery medication. Saka-moto et al. [40] reported that while the numberof acidosis attacks significantly decreased fol-lowing liver transplantation in Japanesepatients with MMA, this was not deemed to be a‘curative’ approach as most patients remainedon a protein-restricted diet. Morioka et al.reported episodes of metabolic stroke [17] andmetabolic episodes [36] following liver trans-plantation. In contrast, Niemi et al. [38] repor-ted no further episodes of metabolicdecompensation following liver transplantationin patients with MMA. patients with MMA whoreceived kidney transplantation or combinedliver/kidney transplantation typically reportedno further metabolic decompensations.McGuire et al. [35] reported the case study of a
Adv Ther (2020) 37:1866–1896 1879
patient who received a combined liver/kidneytransplant at 5 years, with subsequent meta-bolic decompensation at 10 months post-sur-gery; however, no further episodes of metabolicdecompensation were reported.
Can Transplantation ReverseCardiomyopathy in Patients with PA?
Overall, liver transplantation was shown toeffectively reverse baseline cardiomyopathy inapproximately 50% of patients at post-trans-plant follow-up. Romano et al. [22] reportedthat of patients with PA who survived their firstyear of life, a dilated cardiomyopathy developedin six patients at a median age of 7 years (range5–11 years), although this was reversed in twopatients within 1 year following liver trans-plantation. Charbit-Henrion et al. [10] similarlyreported reversal of cardiomyopathy in threepatients with PA following liver transplanta-tion, although three patients with normal heartultrasound prior to transplantation subse-quently developed unexpected heart failure anddied at 1–4 weeks following surgery. Of note,transplantation is typically contraindicated inpatients with severe heart disease.
DISCUSSION
This review has shown that liver, kidney, orcombined liver–kidney transplantation can sig-nificantly improve metabolic outcomes forpatients with PA or MMA. However, data fromretrospective and case studies suggest that thisapproach cannot be considered to be a cure, andall three types of transplantation are associatedwith significant risks of subsequent complica-tions or death.
A number of factors influence the choice oftherapy (liver or kidney transplant alone orcombined liver–kidney transplantation) inpatients with PA or MMA. In general, livertransplantation is deemed to be a suitable treat-ment option for patients with PA and thosepatients with MMA but without renal impair-ment. In contrast, combined liver–kidney
transplantation is considered more suitable inthose patients with MMA and renal impair-ment. In addition, it is important to recognisethe indications and contraindications for theuse of transplantation in PA/MMA. Tradition-ally, transplants have been reserved for the most‘brittle’ patient, in whom it is difficult toachieve reasonable metabolic control or thattheir dietary restriction is very severe and stillnot achieving metabolic control. More recently,there has been a tendency to transplant at anearlier stage, regardless of the level of metaboliccontrol. One reason behind this approach is theincreased availability of transplant units. How-ever, to support the optimal outcome ofpatients with PA/MMA, it is important thatthese transplant units have relevant and suit-able experience in transplanting patients withmetabolic disorders rather than patients withorgan failure alone.
The use of transplantation in patients withPA/MMA typically occurs at a young age,although transplantation at adult age has beenreported when other management approacheshave proven to be unsuccessful. Frequentmetabolic decompensations tend to be the mostcommon indication for transplantation in PA/MMA, although other reasons include subopti-mal metabolic outcomes despite medical ther-apy, elective transplantation in view of thenatural history of the disease, and the preven-tion of ongoing long-term complications of thedisease. Current Scottish Intercollegiate Guide-lines Network (SIGN) guidelines for the man-agement of PA and MMA recommend that liverand/or kidney transplantation should be con-sidered in patients with frequent metabolicdecompensations where the clinical conditionis difficult to stabilise with dietary/pharmaco-logical treatment [1]. A catabolic state or activemetabolic decompensation would be a potentialcontraindication to transplantation; thus clini-cians need to carefully consider related risks andbenefits prior to surgery.
The success of transplantation in PA/MMAremains varied, with substantial rates of associ-ated complications and deaths being reported.While the risk of episodes of metabolic decom-
1880 Adv Ther (2020) 37:1866–1896
pensation are reduced, a proportion of trans-planted patients continue to have episodes(approx. 15%). Martinelli et al. [48] note thatwhile transplanted organs (liver and/or kidney)are an enzyme source, they only partially cor-rect the biochemical defect. However, the smallamount of enzyme activity gained by kidneytransplantation appears sufficient to improvethe metabolic balance in patients with MMA[1]. This could explain why metabolic acidosiswas more commonly reported after liver trans-plantation compared with kidney or combinedliver–kidney transplantation. In addition, therisk of subsequent episodes of metabolic acido-sis following transplantation may be higher inthose patients offered a less restricted dietaryprotein intake, in contrast with those whoremain on a protein-restricted diet and/orreceive appropriate pharmacotherapy to sup-port metabolic stabilisation.
As transplantation is not curative in PA/MMA, it is important to recognise that anyimprovement in metabolic control has to bebalanced with the possibility of complicationsduring surgery and following transplant, alongwith the need for prolonged immunosuppres-sive therapy. A number of factors may influencethe occurrence of post-operative mortality and/or complications. For example, high-levelexpertise of the transplant team and transplantcentre has the potential to reduce post-opera-tive mortality and an experienced team wouldalso recognise that patients with PA/MMAundergoing transplantation would need carefuland prolonged management following surgery.As such, the transplant team should aim towork closely with the metabolic team to sup-port the optimal peri- and post-operative man-agement of the patient’s primary metabolicdisorder, be it PA or MMA. The use ofimmunosuppressive therapy, along with themanagement of any associated tolerabilityissues, also remains important following trans-plantation. Extra-hepatic risks remain followingsurgery in patients with PA and MMA, withtransplantation simply aiming to provide amilder and more manageable phenotype of the
disease. Patients will therefore be required toremain on a protein-restricted diet, albeit a lessstringent one. Of note, patients with PA orMMA should avoid prolonged fasting and dex-trose infusions following transplantation inorder to promote anabolism and prevent meta-bolic decompensation perioperatively. In addi-tion, regular renal surveillance is also advisedpost-transplant in the long term.
Preoperative conditions associated with PAand MMA, such as intellectual disability, pre-existing neurological impairment, and car-diomyopathy, may influence the lifespan of apatient following transplantation. However, theoptimal management of metabolic status bothperioperatively and following transplantationwould serve to minimise any further deteriora-tion of these preoperative conditions. In addi-tion, existing cardiac complications in patientswith PA have the potential to improve follow-ing liver transplantation. It should be notedthat liver and/or kidney transplantation doesnot reverse any neurologic injury that hasaccumulated prior to surgery. Of note, SIGNguidelines suggest that transplantation shouldideally occur prior to any severe neurologicaldeterioration and under stable metabolic con-ditions [1]. Thus, residual neurologic injuryremains a persistent disease complication sug-gesting that postponing a transplant to a laterstage may lead to additional neurologic insultsand possibly inferior neurodevelopmental out-comes. However, post-transplant neurologicaldeterioration in organic acidurias has also beenreported (e.g. [39, 49]. De novo MMA produc-tion in the central nervous system may con-tribute to neurological dysfunction given thatorgan transplantation does not affect the con-centration of MMA in the cerebrospinal fluid[48].
Worsening renal function was reported insome patients with PA following liver trans-plantation, although combined liver–kidneytransplantation appeared more likely to resultin stable renal function. In addition, significantrecovery of cardiac function/reversal of severecardiomyopathy was reported in some patients
Adv Ther (2020) 37:1866–1896 1881
with PA following transplantation, althoughheart failure was reported as the cause of deathin other patients. Thus, cardiac and renalfunction should be assessed before transplanta-tion and monitored closely afterward, withconsideration given to the use of renal-sparingimmunosuppression following surgery.
This review identified that the transplanta-tion process itself was associated with severalsurgical complications, with liver transplanta-tion associated with a higher level of mortalitycompared with kidney and combinedliver–kidney transplantation. HAT remains aserious life-threatening complication in livertransplantation as noted in our findings. Theoverall incidence of HAT following liver trans-plantation varies from 2% to 9% and representsone of the main causes of graft loss and trans-plant recipient mortality [50]. The mechanismof HAT development is not fully understood,although young donor age and small liver graftare reported as risk factors in paediatricdeceased-liver transplantation [51]. Infection,particularly CMV and EBV viremia, was alsocommonly reported, particularly in liver trans-plantation patients. Infection was a predomi-nant cause of post-transplantation death,particularly in patients with MMA, and graftrejection/dysfunction leading to death was alsoreported. The most common reason reported forretransplantation in both patients with PA andMMA was HAT. Other complications whichlimited post-transplantation survival includedcardiac failure and metabolic stroke. Of note,children with organic acidemias appear to be athigher risk of complications from transplanta-tion than other metabolic disorders [52].
When considering the type of liver trans-plantation, SIGN guidelines recommended OLT,as this appears to be associated with fewercomplications compared with auxiliary livertransplantation [1, 36]. However, any benefits oftransplantation must always be weighed againstthe risks associated with organ transplantationalong with the need for long-term immuno-suppression [1, 36]. Toxicity associated with theuse of post-transplantation immunosuppressiveagents does occur, e.g. cyclosporine A andtacrolimus-induced leukoencephalopathy is a
significant complication which may occur attherapeutic levels [53].
The findings from the current narrativereview are in line with preliminary findingsfrom a recent systematic review of the use oftransplantation in patients with PA and MMA.This also demonstrated that while liver and/orkidney transplantation can improve patientoutcome, the potential for increased mortalityrisk and a high risk of complications also needto be considered [54].
This review has a number of limitations.The search strategy used for this review iden-tified 70 suitable references comprising bothabstracts and full papers, although the avail-able level of patient information, assessedclinical parameters, and clinical outcomes var-ied between them. All references were cross-checked to avoid any possible duplication ofdata between abstracts and full papers,although this was limited by the lack of patientinformation and clinical data provided in someof the abstracts meaning that the total numberof transplants performed was actually lowerthan that reported. A number of these refer-ences were pooled studies of metabolic diseasewherein only a few patients had PA or MMA.In addition, duration of follow-up varied sub-stantially between studies, with some studiesnot providing timings of follow-up or compli-cations, and some clinical outcomes of baselineparameters were not reported. For deaths rela-ted to transplantation, some references, par-ticularly abstracts, failed to provide full detailsof the cause of these deaths, which was typi-cally compounded by a lack of specific patientinformation. Likewise, for complications oftransplantation surgery, some studies specifi-cally defined and assessed complications, whileothers failed to do so, or failed to providespecific patient details, leaving the reader tosubjectively interpret any issues related to thetransplantation procedure. For this reason, theoverall data included in this review shouldsimply be used as a guide to the current issuesrelated to transplantation in patients with PAand MMA.
1882 Adv Ther (2020) 37:1866–1896
CONCLUSIONS
In summary, while the use of liver transplanta-tion and combined liver–kidney transplanta-tion appears to benefit some patients with PA orMMA, respectively, this approach does notprovide a metabolic cure and patients remain atrisk from disease-related and transplantation-related complications. Any transplantationprocedure also has an associated mortality risk.Thus, all treatment avenues should ideally beexhausted for PA/MMA before selecting trans-plantation. If liver and/or kidney transplanta-tion remains a viable option, the benefits of thisapproach must be individually and meticu-lously weighed against the risk of perioperativecomplications, including renal and neurologicalprogressive impairment in the post-transplantperiod.
ACKNOWLEDGEMENTS
Funding. Rapid Service and Open Access feesfor this publication were funded by RecordatiRare Diseases, Puteaux, France.
Medical Writing and Editorial Assis-tance. Editorial assistance in the preparation ofthis article was provided by Matthew Joynson ofSpringer Healthcare Ltd. Support for this assis-tance was funded by Recordati Rare Diseases,Puteaux, France.
Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.
Disclosures. Sufin Yap has received fundingfor travel to conferences, honoraria fromRecordati Rare Diseases. Roshni Vara hasreceived honoraria from Recordati Rare Dis-eases. Ana Morais has received honoraria fromRecordati Rare Diseases.
Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.
Data Availability. All data generated oranalysed during this study are included in thispublished article/as supplementary informationfiles.
Open Access. This article is licensed under aCreative Commons Attribution-NonCommercial4.0 International License, which permits anynon-commercial use, sharing, adaptation, dis-tribution and reproduction in any medium orformat, as long as you give appropriate credit tothe original author(s) and the source, provide alink to the Creative Commons licence, and indi-cate if changes were made. The images or otherthird party material in this article are included inthe article’s Creative Commons licence, unlessindicated otherwise in a credit line to the mate-rial. If material is not included in the article’sCreative Commons licence and your intendeduse is not permitted by statutory regulation orexceeds the permitteduse, youwill need toobtainpermission directly from the copyright holder. Toview a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
APPENDIX
See Tables 4 and 5.
Adv Ther (2020) 37:1866–1896 1883
Table4
Overviewof
data
from
PAstudies/case
studies(abstractsonly)
References
nTransplanttype
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Alvarez-Elias
etal.[7]
1LDL/D
DK
Liver transplant:
2(n/s)
Kidney
transplant:
4.9(n/s)
Not
reported
Not
reported
Nephrotic
synd
rome(8
mo
post-liver
transplantation)
withprogression
toESR
D
necessitating
renaltransplant
(n=1)
3(n/a)
Nonereported
Celik
etal.[55]
64LT
[segmental
(n=30),whole
(n=34)]
2.3(0.25–
13)
Not
reported
Not
reported
Graftloss(n
=17)
B10
Graftloss(n
=12;
incl.3
after
retransplantation)
Stroke
(n=1)
Multipleorgan
failure/sepsis
(n=2)
Unknowncauses
(n=1)
Celik
etal.[56]
1LT
Not
specified
Nofurther
metaboliccrises
reported
Not
reported
None
0.6 (0.1–1
.1)
Nonereported
1884 Adv Ther (2020) 37:1866–1896
Table4
continued
References
nTransplanttype
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Curnock
etal.
[57]
14CadavericgraftLT
(n=13,
including4
auxiliary)
Live-relateddonor
LT
(n=1)
2(0.8–8
.0)
Nofurther
metabolic
decompensations
reported
Developmental
progress
(n=11)
C1episodeof
acutecellular
rejection(n
=5)
Metabolicstroke
(n=2)
Cardiom
yopathy
(n=3)
4(2–2
2)Biliaryperitonitis
(n=1)
Acute
orchronic
rejection(n
=1)
PTLD
(n=1)
Duckw
orth
etal.[58]
6LT
3.5±
2.3b
Not
specified
Not
reported
Post-LT
rejection
(n=2;
onemild
andonesevere)
[1
Nonereported
Longo
[59]
3OLT
n/s (0.75–
13)
Nofurther
metaboliccrises
Patientshad
improvem
entsof
developm
ental
milestones
(no
furtherdata)
Nonespecified
n/s (1.6–3
.9)
Nonereported
Moleraet
al.
[60]
4LT
[wholeliver
graft(n
=2),
LDLT
(n=2)]
5.2 (2.9–7
.5)b
Nofurther
metaboliccrises
reported
Stableor
improved
neurological
status
at1-year
postLT
(n=4)
HAT
(n=2)
2.1 (0.31–
3.2)
Nonereported
Nassogneet
al.
[61]
1LDLT
12.5
Nofurther
metaboliccrises
Not
specified
Late-onsetcardiac
failure
(n=1)
4.5(n/a)
Nonereported
Nguyenet
al.
[62]
7OLT
Not
specified
Not
specified
Not
specified
Not
specified
[3(n/s)
Cause
notspecified
(n=1)
Ovchinsky
etal.
[63]
1DDLT
4Nofurther
metaboliccrises
Not
specified
Nonereported
0.8(n/a)
Nonereported
Adv Ther (2020) 37:1866–1896 1885
Table4
continued
References
nTransplanttype
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Quinteroet
al.
[64]
5LT
[wholeliver
graft(n
=3),
LDLT
(n=2)]
5.2 (2.9–7
.5)b
Nofurther
metabolic
decompensations
Stableor
improved
neurological
status
(n=5)
HAT
(n=3)
2.1 (0.31–
3.2)
Nonereported
Reddy
etal.
[65]
4APO
LT
n/s (0.75–
31)
Nofurther
metaboliccrises
Not
specified
HAT
(n=1)
Recurrenceof
symptom
s
second
aryto
portalsteal
(n=1)
n/s(0–6
.3)
Nonereported
Valam
parampil
etal.[66]
5APO
LT
(allleft
auxiliary
liver
transplants)
2.7(n/s)
Nometabolic
episodes
following
transplantation
Progressive
improvem
entin
developm
ent
(n=5)
Nonereported
1.8(n/s)
Nonereported
1886 Adv Ther (2020) 37:1866–1896
Table4
continued
References
nTransplanttype
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Varaet
al.[67]
5LT
[auxiliaryLT
(n=1),
orthotopicleft
lateralsegm
ent
graft(n
=4)]
1.5(0.8–7
)Nofurther
metabolic
decompensations
reported
Moderatelearning
difficulties
(n=2)
Mild
learning
difficulties
(n=2)
Developmental
delaywitha
probable
metabolicstroke
(resulting
inmild
hemiplegiaand
focalseizures)
(n=1)
Recurrent
herpes
simplex
virus
infection(n
=2)
EBV-positive
PTLD
(n=1)
Probablemetabolic
stroke
resulting
in
mild
hemiplegia
andfocalseizures
(n=1)
5.8(1–1
4)Nonereported
Adv Ther (2020) 37:1866–1896 1887
Table4
continued
References
nTransplanttype
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Varaet
al.[68]
13LT
[leftlateral
segm
entgrafts
(n=7),left
lateralsegm
ent
(n=2),right
lobe
auxiliary
grafts(n
=2),
wholegraft
(n=1),live
relateddonor
(n=1)]
2(1–7
)Nometabolic
decompensations
reported
in9
survivingpatients
Noevidence
of
cardiomyopathy
in9surviving
patients
HAT
requiring
retransplantation
(n=1)
Chronic
cholangiopathy
requiring
retransplantation
(n=1)
Pulmonary
haem
orrhage
(n=1)
Biliarysepsis
(n=1)
4(0.6–2
0.5)
Pulmonary
haem
orrhage
(n=1;
29days
postLT)
Biliarysepsis(n
=1;
42days
postLT)
Lym
phoproliferative
disorder
(n=1;
14yearspostLT)
Walkeret
al.
[69]
5LT
1.8 (0.75–
7.0)
Not
reported
Not
reported
Impaired
systolic
function
(n=1)
4.25 (0–1
0.5)
Nonereported
APO
LTauxiliarypartialorthotopiclivertransplantation,DDLTdeceased-donor
livertransplantation,EBVEpstein–B
arrvirus,ESR
Dend-stagerenaldisease,H
AT
hepaticartery
stenosis,KT
kidn
eytransplantation,
LDL/D
DK
living-donorliver/deceased-donorkidn
ey,LDLT
living-donorliver
transplantation,
LT
liver
transplantation,
OLTorthotopicliver
transplantation,
PTLD
post-transplantlymphoproliferativedisease,n/anotavailable,n/snotspecified
aVarious
typesof
liver
transplantationused
bMean(range)transplant
ageshow
n
1888 Adv Ther (2020) 37:1866–1896
Table5
Overviewof
data
from
MMA
studies/case
studies(abstractsonly)
References
nTransplant
type
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Almeida
etal.[70]
1LT
10(n/a)
Not
reported
Post-LT
VIQ
,PIQ
andFSIQ
scores
displayedapositive
change
(VIQ
=91;
PIQ
=84;
FSIQ
=84)
Nonereported
1(n/a)
Nonereported
Barshop
etal.[71]
1DLT
28(n/a)
Nometabolic
decompensations
Not
specified
Nonereported
0.75
(n/a)
Nonereported
Boyer
etal.
[72]
4DDKT
5.7(5–1
0)Num
berperyear
dram
atically
decreased(nodata
specified)
Neurological
complications
stabilised(nofurther
deterioration)
Hepatocarcino
ma
(n=1)
n/s(0.5–3
.0)
Hepatocarcinoma(n
=1)
Corno
etal.
[47]
1LT
9(n/a)
Fatalm
etaboliccrisis
(n=1)
Not
reported
Fatalmetabolic
crisis(n
=1)
Not
reported
Fatalmetaboliccrisis
(n=1)
Fukuda
etal.[73]
10LDLT
n/s(0.6–7
)Severe
metabolic
acidosis(n
=2)
Nofurther
metabolic
decompensations
insurviving
patients(n
=9)
Nosignificant
improvem
entin
patientIQ
Viralinfection
(n=6)
Severe
metabolic
acidosis(n
=2)
3.5(n/s)
Severe
metabolicacidosis
followingrejectionand
sepsis(n
=2)
Jiangand
Sun[74]
7LDLT
(n=3)
DDLT
(n=4)
Not
specified
Nofurther
metaboliccrises
Not
specified
Nonereported
Not
specified
Nonereported
Adv Ther (2020) 37:1866–1896 1889
Table5
continued
References
nTransplant
type
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Matsumoto
etal.[75]
1LDKT
26(n/a)
Nofurther
metaboliccrises
Not
specified
Nonereported
0.5(n/a)
Nonereported
Nakajim
a
etal.[76]
1LDLT
5.3(n/a)
Markedreductionof
metabolic
decompensation
(noadditional
data)
Leigh’sencephalopathy
(n=1)
Leigh’s
encephalopathy
(n=1)
[1.5(n/a)
Nonereported
Shenoy
etal.[77]
5KT
10.8 (5.8–1
7.8)
Noepisodes
of
metabolic
decompensation
reported
inthe
immediate
perioperative
period
Neurological
deterioration
(n=1)
Severe
haem
orrhagic
pancreatitis
(n=1)
Bacterial
endocarditis
(n=1)
Progressive
deteriorationin
graftfunction
(n=1)
Pancreatitis
(n=1)
Neurological
deterioration
(n=1)
B6
Severe
haem
orrhagic
pancreatitisleadingto
death(n
=1)
Bacterialendocarditis,
progressivedeterioration
ingraftfunction,
pancreatitis,and
neurological
deterioration(n
=1)
1890 Adv Ther (2020) 37:1866–1896
Table5
continued
References
nTransplant
type
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Sissaoui
etal.[78]
13KT
(n=7)
Com
bined
LT/K
T
(n=5)
LT
(n=1)
KT:9.7
(5–1
7)
Com
bined
LT/K
T:14
(6–1
9)
LT:n/s(n/a)
Not
specified
LT/K
T:
Axonalneuropathy
(n=1)
Myoclonus
(n=1)
KT:renalfailure
recurrence
(n=4)
Com
binedLT/
KT:graft
rejection(n
=1)
Biliaryproblems
(n=1)
Axonal
neuropathy
(n=1)
Myoclonus
(n=1)
LT:none
reported
KT:5(n/s)
Com
bined
LT/K
T:1.5
(n/s)
LT:0.5(n/a)
Nonereported
Yam
amoto
etal.[79]
1KT
26(n/a)
Nofurtherepisodes
ofmetabolic
decompensation
reported
Nofurther
neurological
deterioration(at
10monthspost-
transplant)
Nonereported
0.8(n/a)
Nonereported
Adv Ther (2020) 37:1866–1896 1891
Table5
continued
References
nTransplant
type
aMedian
(range)
transplant
age(years)
Post-transplant
metabolic
control
Post-transplant
neurological
health
Com
plications
Median
(range)
duration
offollo
w-up
(years)
Deaths(cause
and
number)
Yoshino
etal.[80]
2LT
6.3(5.2–7
.3)
Not
specified
Episodesof
quick
torsionalmovem
ents
ofthehead
(n=1)
Tonicseizure(n
=1)
Episodesof
quick
torsional
movem
entsof
thehead
(n=1)
Tonicseizure
(n=1)
Weaknessof
the
rightextrem
ities
andflexion
ofthe
rightupper
extrem
ity
(n=1)
2.3(2–2
.6)
Nonereported
ALTauxiliary
liver
transplantation,
CMVcytomegalovirus,K
Tkidn
eytransplantation,
LDLTliving-donorliver
transplantation,
LTliver
transplantation,
LT/K
Tliver/kidneytransplantation,
OLTorthotopicliver
transplantation,
n/anotavailable,n/snotspecified
aVarious
typesof
liver
transplantationused
1892 Adv Ther (2020) 37:1866–1896
REFERENCES
1. Baumgartner MR, Horster F, Dionisi-Vici C, et al.Proposed guidelines for the diagnosis and manage-ment of methylmalonic and propionic acidemia.Orphanet J Rare Dis. 2014;9:130.
2. Kim IK, Niemi AK, Krueger C, et al. Liver trans-plantation for urea cycle disorders in pediatricpatients: a single-center experience. PediatrTranspl. 2013;17:158–67.
3. Li M, Dick A, Montenovo M, Horslen S, Hansen R.Cost-effectiveness of liver transplantation inmethylmalonic and propionic acidemias. LiverTranspl. 2015;21:1208–18.
4. Fabuioli J, Daina E, D’Antiga L, et al. Monogenicdisease that can be cured by liver transplantation.J Hepatol. 2013;59:595–612.
5. Shneider BL. Pediatric liver transplantation inmetabolic disease: clinical decision making. PediatrTranspl. 2002;6:25–9.
6. Mazariegos G, Shneider B, Burton B, et al. Livertransplantation for pediatric metabolic disease. MolGenet Metab. 2014;111:418–27.
7. Alvarez-Elias AC, Williams A, Hebert D. Kidneytransplantation after liver transplantation in apatient with propionic acidemia: managementchallenges. Blood Purif. 2018;45:302–3.
8. Arrizza C, De Gottardi A, Foglia E, et al. Reversal ofcardiomyopathy in propionic acidemia after livertransplantation: a 10-year follow-up. Transpl Int.2015;28:1447–500.
9. Barshes NR, Vanatta JM, Patel AJ, et al. Evaluationand management of patients with propionic acid-emia undergoing liver transplantation: a compre-hensive review. Pediatr Transpl. 2006;10:773–81.
10. Charbit-Henrion F, Lacaille F, McKiernan P, et al.Early and late complications after liver transplan-tation for propionic acidemia in children: a twocenters study. Am J Transpl. 2015;15:786–91.
11. Critelli K, McKiernan P, Vockley J, et al. Livertransplantation for propionic acidemia andmethylmalonic acidemia: perioperative manage-ment and clinical outcomes. Liver Transpl. 2018;24:1260–70.
12. Kasahara M, Sakamoto S, Kanazawa H, et al. Living-donor liver transplantation for propionic acidemia.Pediatr Transpl. 2012;16:230–4.
13. Kasahara M, Sakamoto S, Horikawa R, et al. Livingdonor liver transplantation for pediatric patients
with metabolic disorders: the Japanese multicenterregistry. Pediatr Transpl. 2014;18:6–15.
14. Kayler LK, Merion RM, Lee S, et al. Long-term sur-vival after liver transplantation in children withmetabolic disorders. Pediatr Transpl. 2002;6:295–300.
15. Lam C, Desviat LR, Perez-Cerda C, et al. 45-Year-oldfemale with propionic acidemia, renal failure, andpremature ovarian failure; late complications ofpropionic acidemia? Mol Genet Metab. 2011;103:338–40.
16. Moguilevitch M, Delphin E. Domino liver trans-plantation from a child with propionic acidemia toa child with idiopathic fulminant hepatic failure.Case Rep Transpl. 2018;2018:1897495.
17. Morioka D, Kasahara M, Takada Y, et al. Livingdonor liver transplantation for pediatric patientswith inheritable metabolic disorders. Am J Transpl.2005;5:2754–63.
18. Nagao M, Tanaka T, Morii M, et al. Improved neu-rologic prognosis for a patient with propionicacidemia who received early living donor livertransplantation. Mol Genet Metab. 2013;108:25–9.
19. Quintero J, Molera C, Juamperez J, et al. The role ofliver transplantation in propionic acidemia. LiverTranspl. 2018;24:1736–45.
20. Rammohan A, Gunasekaran V, Reddy MS, Rela M.The role of liver transplantation in propionic acid-emia. Liver Transpl. 2019;25:176–7.
21. Rela M, Battula N, Madanur M, et al. Auxiliary livertransplantation for propionic acidemia: a 10-yearfollow-up. Am J Transpl. 2007;7:2200–3.
22. Romano S, Valayannopoulos V, Touati G, et al.Cardiomyopathies in propionic aciduria are rever-sible after liver transplantation. J Pediatr. 2010;156:128–34.
23. Schlenzig JS, Poggi-Travert F, Laurent J, et al. Livertransplantation in two cases of propionic aci-daemia. J Inher Metab Dis. 1995;18:448–61.
24. Shanmugam NP, Valamparampil JJ, Srinivas ReddyM, et al. Auxiliary partial orthotopic liver trans-plantation for monogenic metabolic liver diseases:single-centre experience. JIMD Rep. 2019;45:29–36.
25. Vara R, Turner C, Mundy H, et al. Liver transplan-tation for propionic acidemia in children. LiverTranspl. 2011;17:661–7.
26. Yorifuji T, Kawai M, Mamada M, et al. Living-donorliver transplantation for propionic acidaemia. J In-herit Metab Dis. 2004;27:205–10.
Adv Ther (2020) 37:1866–1896 1893
27. Brassier A, Boyer O, Valayannopoulos V, et al. Renaltransplantation in 4 patients with methylmalonicaciduria: a cell therapy for metabolic disease. MolGenet Metab. 2013;110:106–10.
28. Chen PW, Hwu WL, Ho MC, et al. Stabilization ofblood methylmalonic acid level in methylmalonicacidemia after liver transplantation. PediatrTranspl. 2010;14:337–41.
29. Clothier JC, Chakrapani A, Preece MA, et al. Renaltransplantation in a boy with methylmalonic aci-daemia. J Inherit Metab Dis. 2011;34:695–700.
30. Duclaux-Loras R, Bacchetta J, Berthiller J, et al.Pediatric combined liver–kidney transplantation: asingle-center experience of 18 cases. PediatrNephrol. 2016;31:1517–29.
31. Hirotsu A, Kusudo E, Mori N, et al. Successful peri-operative management of living-donor liver trans-plantation for a patient with severe methylmalonicacidemia: a case report. JA Clin Rep. 2018;4:83.
32. Khanna A, Gish R, Winter SC, et al. Successfuldomino liver transplantation from a patient withmethylmalonic acidemia. JIMD Rep. 2016;25:87–94.
33. Lubrano R, Elli M, Rossi M, et al. Renal transplant inmethylmalonic acidemia: could it be the bestoption? Report on a case at 10 years and review ofthe literature. Pediatr Nephrol. 2007;22:1209–14.
34. Lubrano R, Perez B, Elli M. Methylmalonic acidemiaand kidney transplantation. Pediatr Nephrol.2013;28:2067–8.
35. McGuire PJ, Lim-Melia E, Diaz GA, et al. Combinedliver–kidney transplant for the management ofmethylmalonic aciduria: a case report and review ofthe literature. Mol Genet Metab. 2008;93:22–9.
36. Morioka D, Kasahara M, Horikawa R, et al. Efficacyof living donor liver transplantation for patientswith methylmalonic acidemia. Am J Transpl.2007;7:2782–7.
37. Nagarajan S, Enns GM, Millan MT, et al. Manage-ment of methylmalonic acidaemia by combinedliver-kidney transplantation. J Inherit Metab Dis.2005;28:517–24.
38. Niemi AK, Kim IK, Krueger CE, et al. Treatment ofmethylmalonic acidemia by liver or combinedliver-kidney transplantation. J Pediatr.2015;166(1455–61):e1.
39. Nyhan WL, Gargus JJ, Boyle K, Selby R, Koch R.Progressive neurologic disability in methylmalonicacidemia despite transplantation of the liver. Eur JPediatr. 2002;161:377–9.
40. Sakamoto R, Nakamura K, Kido J, et al. Improve-ment in the prognosis and development of patientswith methylmalonic acidemia after living donorliver transplant. Pediatr Transpl. 2016;20:1081–6.
41. Spada M, Calvo PL, Brunati A, et al. Early livertransplantation for neonatal-onset methylmalonicacidemia. Pediatrics. 2015;136:e252–e256256.
42. Stevenson T, Millan MT, Wayman K, et al. Long-term outcome following pediatric liver transplan-tation for metabolic disorders. Pediatr Transpl.2010;14:268–75.
43. Edwards EB, Roberts JP, McBride MA, et al. Theeffect of the volume of procedures at transplanta-tion centers on mortality after liver transplantation.N Engl J Med. 1999;341:2049–53.
44. Nichols TJ, Price MB, Villarreal JA, et al. Mostpediatric transplant centers are low volume, adult-focused, and in proximity to higher volume pedi-atric centers. J Pediatri Surg. 2019;5:6. https://doi.org/10.1016/j.jpedsurg.2019.10.019.
45. Rana A, Pallister Z, Halazun K, et al. Pediatric livertransplant center volume and the likelihood oftransplantation. Pediatrics. 2015;136:e99–e107.
46. Tracy ET, Bennett KM, Danko ME, et al. Low vol-ume is associated with worse patient outcomes forpediatric liver transplant centers. J Pediatri Surg.2010;45:108–13.
47. Corno V, Lucianetti A, Stroppa P, et al. Pediatricliver-kidney transplantation: a single center expe-rience. Transpl Int. 2011;24(Suppl 2):318 (AbstractP-370).
48. Martinelli D, Liccardo D, Catesini G, et al. PersistentCSF biochemical abnormalities in transplantedpatients with methylmalonic aciduria: a longitudi-nal study. J Inherit Metab Dis. 2018;41(Suppl 1):S126 (Abstract P-190).
49. Van Calcar SC, Harding CO, Lyne P, et al. Renaltransplantation in a patient with methylmalonicacidaemia. J Inherit Metab Dis. 1998;21:729–37.
50. Abdullah AA, Moustafa MM, Simon RB. Anticoag-ulation and antiplatelets as prophylaxis for hepaticartery thrombosis after liver transplantation. WorldJ Hepatol. 2015;7:1238–43.
51. Ma N, Song Z, Dong C, et al. Risk factors of hepaticartery thrombosis in pediatric deceased donor livertransplantation. Pediatr Surg Int. 2019;35:853–9.
52. Leonard JV, Walter JH, McKiernan PJ. The man-agement of organic acidaemias: the role of trans-plantation. J Inherit Metab Dis. 2001;24:309–11.
1894 Adv Ther (2020) 37:1866–1896
53. Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ trans-plant recipients. Transplantation. 2000;69:467–72.
54. Williams M, Dionisi-Vici C, Molema F. Organtransplantation in individuals with urea cycle dis-orders and classic organic acidurias. In: Presenta-tion at 8th Annual E-IMD Members Meeting, 13thNovember 2018. Brussels.
55. Celik N, Soltys K, Bond G, et al. Liver transplanta-tion for propionic acidemia: a review of the UnitedStates Scientific Registry for Transplant Recipients(SRTR) and non-US case series. Am J Transpl.2016;16(suppl 3):766 (Abstract D210).
56. Celik N, Ganoza A, Bond G, et al. Allograft dominoliver transplantation for selected metabolic disor-ders. Pediatr Transpl. 2017;21(Suppl 1):3 (Abstract202.4).
57. Curnock R, Vara R, Hadzic N, Heaton N, Vilca-Me-lendez H, Dhawan A. Liver transplantation in pro-pionic acidaemia: a single centre experience in theUK. J Inherit Metab Dis. 2018;41(Suppl 1):S124(Abstract P-185).
58. Duckworth C, Yazigi N. Hospitalizations, dietarytreatment, and metabolic markers in propionicacidemia patients pre-and post-liver transplant.Mol Genet Metab. 2018;123:227–8.
59. Longo N. Effect of liver transplantation on hyper-ammonemia and metabolic control in propionicacidemia. J Inborn Errors Metab Screen. 2017;5:185(Abstract 410).
60. Molera C, Quintero Bernabeu J, Juamperez Goni J,et al. Liver transplantation in propionic acidemia.J Pediatr Gastroenterol Nutr. 2017;64(Suppl 1):723(Abstract H-P-065).
61. Nassogne M, Vincent M, Reding R, et al. Late-onsetcardiac failure after liver transplantation in onepatient with propionic acidemia. J Inherit MetabDis. 2015;38(Suppl 1):S161–S162162.
62. Nguyen NT, Harring TR, O’Mahony C, et al. Propi-onic acidemia and orthotopic liver transplantation:the UNOS experience. Am J Transpl. 2011;11(Suppl2):496–7.
63. Ovchinsky N, Cunningham RM, Kogan-LibermanD, et al. Expanding the utilization of metaboliclivers for domino transplantation: successful dom-ino liver transplant from a patient with propionicacidemia. Hepatology. 2016;64(Suppl 1):700A–701A (abstract 1399).
64. Quintero J, Molera C, Juemparez J, et al. The role ofliver transplantation for propionic acidemia in
children. Pediatric Transpl. 2017;21(suppl 1):50(Abstract P129).
65. Reddy M, Shanmugham N, Varghese J, et al. Aux-iliary partial orthotopic liver transplantation(APOLT): a safe and effective alternative to ortho-topic liver transplantation for patients with acuteliver failure and non-cirrhotic metabolic liver dis-ease. Transplantation. 2016;100(Suppl 1):S6–47(Abstract 325.8).
66. Valamparampil JJ, et al. Preserving the native liverfor future; auxiliary partial orthotopic liver trans-plantation (APOLT) for monogenic metabolic liverdisease (MLD). Hepatol Int. 2018;12(2):S644–S645.
67. Vara R, Turner C, Champion M, et al. Liver trans-plantation for propionic acidemia in children. J Pe-diatr Gastroenterol Nutr. 2010;50(suppl 2):E163–E164 (Abstract PO-H-355).
68. Vara R, Mundy H, Champion M, et al. Mediumterm outcome of liver transplantation for childrenwith propionic acidaemia. Hepatology. 2016;64(-suppl 1):335A–6A (Abstract 676).
69. Walker PLC, Miller O, Vara R. Role of cardiacmonitoring in patients with propionic acidaemiafollowing liver transplantation: a retrospectivereview. J Inherit Metab Dis. 2014;37(Suppl 1):S89(Abstract P-172).
70. Almeida J, Garcia P, Ferreira F, Faria A, Goncalves I,Diogo L. Improvement in neuropsychological out-comes of a child with methylmalonic acidemia afterliver transplantation. J Inherit Metab Dis.2018;41(Supplement 1):S128 (Abstract P-196).
71. Barshop BA, Nyhan WL, Khanna A. Domino livertransplantation in methylmalonic acidemia. J In-herit Metab Dis. 2012;35(Suppl 1):S9 (AbstractO-026).
72. Boyer O, Krug P, Guest G, Valayannopoulos V,Niaudet P. Methylmalonic acidemia: a new indica-tion for preemptive renal transplantation? PediatrNephrol. 2010;25:1815 (Abstract 100).
73. Fukuda A, Kasahara M, Sakamoto S, et al. Evalua-tion of living donor liver transplantation forpatients with methylmalonic acidemia. J PediatrGastroenterol Nutr. 2011;52(suppl 1):E201.
74. Jiang Y, Sun L. Perioperative characteristics of livertransplantation for methylmalonic acidemia andmanagement experience. Transplant. 2018;102(-suppl):317–8 (Abstract LB P-041).
75. Matsumoto I, Kenmochi T, Maruyama M, et al.Renal transplantation for chronic renal failure inmethylmalonic acidemia: a case report. Transplan-tation. 2012;94(10S):859 (Abstract 795).
Adv Ther (2020) 37:1866–1896 1895
76. Nakajima Y, Ito T, Ichiki S, et al. Case study ofmethylmalonic acidemia presenting with acuteencephalopathy associated with basal nuclei lesions20 months after liver transplantation from a livingdonor. J Inherit Metab Dis. 2010;33(Suppl 1):S54(Abstract 131-P).
77. Shenoy M, Jameson E, Webb N. Single centreexperience of isolated kidney transplantation inmethylmalonic aciduria. Pediatr Nephrol.2015;30(9):1708 (Abstract P-431).
78. Sissaoui S, Brassier A, Chardot C, et al. Early livertransplantation or combined liver-kidney
transplantation: what is the best solution formethylmalonic acidemia? J Pediatr GastroenterolNutr. 2017;64(suppl 1):648 (Abstract H-eP-030).
79. Yamamoto S, et al. Kidney transplantation in a26-year-old Japanese male with methylmalonicaciduria presenting end stage renal failure (SecondReport). J Inherit Metab Dis. 2012;35(Suppl 1):S64.
80. Yoshino M, Oohira T, Watanabe Y, Okada J. Neu-rological deterioration in two patients withmethylmalonic aciduria following liver transplan-tation and subsequent relaxation of natural proteinintake. J Inherit Metab Dis. 2010;1(33):S46.
1896 Adv Ther (2020) 37:1866–1896