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: sufin.yap@nhs.net

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