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REPORT
Liver transplant in ethylmalonic
encephalopathy: a new treatment
for an otherwise fatal disease
Carlo Dionisi-Vici,
1,
Daria Diodato,
1,2,
Giuliano Torre,
3
Stefano Picca,
4
Rosanna Pariante,
5
Sergio Giuseppe Picardo,
5
Ivano Di Meo,
6
Cristiano Rizzo,
1
Valeria Tiranti,
6
Massimo Zeviani
7
and Jean De Ville De Goyet
8
These authors contributed equally to this work.
Ethylmalonic encephalopathy is a fatal, rapidly progressive mitochondrial disorder caused by ETHE1 mutations, whose peculiar
clinical and biochemical features are due to the toxic accumulation of hydrogen sulphide and of its metabolites, including thio-
sulphate. In mice with ethylmalonic encephalopathy, liver-targeted adeno-associated virus-mediated ETHE1 gene transfer dramat-
ically improved both clinical course and metabolic abnormalities. Reasoning that the same achievement could be accomplished by
liver transplantation, we performed living donor-liver transplantation in an infant with ethylmalonic encephalopathy. Unlike the
invariably progressive deterioration of the disease, 8 months after liver transplantation, we observed striking neurological improve-
ment with remarkable achievements in psychomotor development, along with dramatic reversion of biochemical abnormalities.
These results clearly indicate that liver transplantation is a viable therapeutic option for ETHE1 disease.
1 Division of Metabolism, Department of Paediatric Medicine, Bambino Gesu
`Children’s Research Hospital IRCCS, Rome, Italy
2 Neuromuscular and Neurodegenerative Diseases Unit, Bambino Gesu
`Children’s Research Hospital IRCCS, Rome, Italy
3 Division of Hepatology and Gastroenterology, Bambino Gesu
`Children’s Research Hospital IRCCS, Rome, Italy
4 Division of Nephrology and Dialysis, Bambino Gesu
`Children’s Research Hospital IRCCS, Rome, Italy
5 Division of Intensive Care and Anaesthesia, Bambino Gesu
`Children’s Research Hospital IRCCS, Rome, Italy
6 Unit of Molecular Neurogenetics-Pierfranco and Luisa Mariani Centre for the Study of Mitochondrial Disorders in Children,
Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy
7 MRC-Mitochondrial Biology Unit, Cambridge, UK
8 Department of Surgery and Transplantation, Bambino Gesu
`Children’s Research Hospital IRCCS, Rome, Italy
Correspondence to: Carlo Dionisi-Vici,
Division of Metabolism,
Bambino Gesu
`Children’s Research Hospital IRCCS,
Piazza Sant’Onofrio 4,
00165 Rome, Italy
E-mail: carlo.dionisivici@opbg.net
Keywords: ethylmalonic encephalopathy; liver transplant; mitochondrial disorders treatment
doi:10.1093/brain/aww013 BRAIN 2016: Page 1 of 7 |1
Received September 22, 2015. Revised December 14, 2015. Accepted December 16, 2015.
ßThe Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
Brain Advance Access published February 25, 2016
by guest on March 1, 2016http://brain.oxfordjournals.org/Downloaded from
Introduction
Ethylmalonic encephalopathy is a rare, devastating, invari-
ably fatal, multisystem infantile disorder caused by loss of
function mutations in ETHE1, inherited in an autosomal
recessive mode (Burlina et al., 1991,1994;Tiranti et al.,
2004). More than 100 families with ethylmalonic encephal-
opathy and 60 different mutations have been reported.
ETHE1 encodes a mitochondrial sulphur dioxygenase
involved in the catabolism of hydrogen sulphide
(Hildebrandt and Grieshaber, 2008;Tiranti et al., 2009).
Because of sulphur dioxygenase impairment, hydrogen sul-
phide and its derivative thiosulphate accumulate in tissues
and body fluids. Hydrogen sulphide, which in trace amounts
is involved as a gas-mediator in vessel tone regulation, at
higher concentrations is extremely toxic and induces direct
damage to cell membranes, including vascular endothelial
cells and mucosal cells of the large intestine. It also inhibits
both cytochrome coxidase, blocking mitochondrial respir-
ation and increasing lactic acid, and short-chain acyl-CoA
dehydrogenase, with consequent elevation of ethylmalonate
and C4/C5 acylcarnitine esters, predominantly in muscle and
brain (Tiranti et al.,2009;Di Meo et al.,2011). The major
clinical features of ethylmalonic encephalopathy are hydro-
gen sulphide mediated, and include diffuse microvasculature
injury, consisting of petechial purpura, orthostatic acrocyan-
osis, haemorrhagic suffusions of mesothelial surfaces and
intestinal mucosa associated with chronic diarrhoea. The
vasculopathy is also responsible for multiple necrotic brain
lesions, which lead to early-onset psychomotor regression,
seizures and global neurological impairment configuring in
the late stage of the disease the picture of severe psycho-
motor delay with spastic tetraparesis (Burlina et al.,1991,
1994;Mineri et al., 2008;Giordano et al.,2012). As the
major source of hydrogen sulphide production in mammals
is the anaerobic bacterial flora of the large intestine
(Flannigan et al.,2011), and glutathione can act as an intra-
cellular buffer of hydrogen sulphide, a combination of
metronidazole—an antibiotic against anaerobic bacteria
and parasites—and N-acetyl cysteine—a cell-permeable
precursor of glutathione—have been used in ethylmalonic
encephalopathy, with some improvement, especially in
extra-neurological symptoms (Viscomi et al., 2010).
Nevertheless, the prognosis of ethylmalonic encephalopathy
remains poor, with rapid progression towards severe neuro-
developmental regression and death usually before the age of
10 years.
Recently, we demonstrated the efficacy of liver-specific,
adeno-associated virus-mediated expression of human wild-
type ETHE1 as a therapy in an Ethe1
-/-
mouse model, which
faithfully recapitulates the biochemical and clinical hall-
marks of the human disease (Di Meo et al.,2012). This
genetic correction, limited to liver tissue, was associated
with marked prolongation of lifespan as compared to un-
treated Ethe1
-/-
littermates, dramatic amelioration of clinical
conditions and normalization of several disease biomarkers,
including plasma thiosulphate, ethylmalonate and lactate.
The rationale for this experimental procedure relies on the
knowledge that the liver acts as a filter, draining, through
the portal system, the blood from most of the gastrointes-
tinal tract, including large intestine, containing toxic hydro-
gen sulphide produced by the anaerobic bacterial flora. As
clearance of hydrogen sulphide is impaired in Ethe1
-/-
liver,
its restoration by adeno-associated virus-mediated, liver-spe-
cific gene therapy, can result in effective conversion of
hydrogen sulphide into harmless sulphate. However, ap-
proval of adeno-associated virus-based gene treatment in
humans requires a lengthy and complex procedure through
either the European Medicines Agency or its American
equivalent, the US Food and Drug Administration.
Following our findings in the Ethe1
-/-
murine model, we
reasoned that liver transplantation could also ameliorate
human ethylmalonic encephalopathy. Liver transplantation is
an approved procedure, which can replace missing enzymatic
function and clear accumulation of toxic compounds in sev-
eral inherited metabolic disorders (Macchiaiolo et al., 2012).
Case report
A 7-month-old girl, the second child of unrelated parents
from Moscow, Russia, was referred to the Bambino Gesu
`
Hospital, presenting with clinical and biochemical hall-
marks of ethylmalonic encephalopathy. Her older sister
died at 8 months of age, soon after a general anaesthesia
for an MRI performed to investigate her neurological im-
pairment. Molecular genetic analysis of ETHE1 from blood
DNA revealed the presence of a homozygous mutation
c.131-132delAG (Supplementary Fig. 1), which causes the
formation of a premature stop codon. This mutation is
present in European and East Asian populations and has
a global estimated frequency of 2:119 000 (ExAc database);
it was reported in a previous patient in compound hetero-
zygosity with another missense mutation (Tiranti et al.,
2004) and is associated with the absence of the ETHE1
protein (Supplementary Fig. 1).
The neurological examination in this baby showed moder-
ate psychomotor delay, mild drowsiness and axial hypotonia
with spasticity of lower limbs. Fixation and pursuit were
normal. Although she had acquired head control, she still
failed to sit unaided; she was able to reach for objects with
both arms, and grasping was possible even if slightly abnor-
mal. The Gross Motor Function Measure (GMFM-66) scale
scored 12. The baby showed good social interaction, but lan-
guage skills were limited to babbling. She had severe petechial
purpura and orthostatic acrocyanosis. Brain MRI demon-
strated initial involvement of basal ganglia (Fig. 1A).
Biochemically, blood lactic acid levels were very high (up to
81 mg/dl; normal values (nv) = 6–22), as well as C4- (1.47–
1.53 mmol/l; nv 50.9) and C5- (0.45–0.60 mmol/l; nv 50.3)
acylcarnitine esters, and plasma thiosulphate (35 mmol/l;
nv 54).Ethylmalonicacidwasincreasedinurine(169–
210 mmol/mol creatinine; nv 520).
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We attempted treatment with metronidazole (30 mg/kg/
day) and N-acetyl cysteine (100 mg/kg/day); however, the
biochemical abnormalities persisted: blood lactic acid 32–
60 mg/dl (nv = 6–22), C4-carnitine 1.21–1.46 mmol/l
(nv 50.9), C5-carnitine 0.62–0.84 mmol/l (nv 50.3),
plasma thiosulphate = 21–40 mmol/l (nv 54), urinary ethyl-
malonic acid = 115–280 mmol/mol creatinine (nv 520).
Based on our results on liver-specific adeno-associated virus-
mediated gene therapy of murine ethylmalonic encephalop-
athy, we proposed liver transplantation as a therapeutic
option for human ethylmalonic encephalopathy and a suitable
protocol was approved by the local Ethics Committee.
Screening of the patient and her parents, both heterozygous
for the mutation, showed an ABO identity between the baby
girl and her mother, who volunteered to donate a portion of
her liver. The baby underwent liver transplantation at age 9
months, with her mother as a living donor.
Surgery in the living donor consisted of a standard pro-
curement of the left lateral segment of the liver, and conven-
tional caval, portal and arterial anastomosis without vascular
graft interposition, with a duct-to-duct biliary reconstruction.
To reduce the bulk of metabolites during surgery, the pro-
cedure was performed under continuous veno-venous haemo-
dialysis; it was uncomplicated and both intra- and immediate
postoperative ultrasonography-Doppler examinations showed
adequate vascular perfusion of the graft.
Results
The baby showed progressive improvement in the immediate
postoperative period. The daily monitoring of blood and
urine metabolites carried out from several days before,
during the surgical procedure and through the first 2 weeks
Figure 1 Neuroradiological and clinical follow-up. Brain MRI T
2
-weighted sections in a patient with ethylmalonic encephalopathy before
liver transplantation showing (A) fronto-temporal atrophy with hyperintense lesions involving bilaterally the putamen and caudate nucleus, and
(B) 3- and (C) 8 months after liver transplantation, the lack of lesion’s progression with reduction of cortical atrophy. (D) Serial evaluation of
GMFM-66 score in the patient before and at different times after liver transplantation.
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after the intervention showed rapid reduction of plasma thio-
sulphate and urinary ethylmalonate (Fig. 2A and B). Soon
after the intervention and during the follow-up, she continued
to be treated with carnitine, metronidazole and the local
standard immunosuppressive treatment (basiliximab induction
and tacrolimus long-term monotherapy). Her clinical, neuro-
logical and metabolic features were periodically monitored.
Hepatic function remained constantly in the normal range.
Figure 2 Biochemical follow-up. Serial evaluation of blood and urinary metabolite concentrations before liver transplantation, at liver
transplantation (on dialysis) and at follow-up. (A) Plasma thiosulphate, (B) plasma lactate and (C) urinary ethylmalonic acid levels. Dotted lines
indicate upper normal levels. LT = liver transplant.
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Values of thiosulphate and ethylmalonate have consistently
decreased to nearly normal levels during the follow-up,
which has now reached 1 year since the day of surgery
(Fig. 2A and B). Blood lactate improved but its concentration
still remains above the reference limit (Fig. 2C). After liver
transplantation, blood acylcarnitines levels fluctuated, but
they did not return to normal levels (C4 0.8–1.2 mmol/l;
nv 50.9; C5 0.4–0.5 mmol/l; nv 50.3). However, these
values that represent a target biomarker in the diagnostic pro-
cess are difficult to interpret in the disease course as the pa-
tient received carnitine supplementation to maximize the
clearance of C4 and C5 carnitine species soon after the diag-
nosis and during the entire follow-up period. The dramatic
reversion to normal of most blood and urine metabolites was
associated with remarkable and consistent amelioration of the
clinical condition. Two months after liver transplantation the
baby was able to sit unaided for some seconds, roll over from
supine-to-prone positions on both sides, and the GMFM-66
increased to 15.6. At 16 months of age, the neurological
examination showed further progress in motor milestones,
as she stably maintained the sitting position and was able
to walk a few steps with bilateral support, albeit with a spas-
tic gait. GMFM-66 scored 31.6 (Fig. 1D). In recent years, the
Gross Motor Function Measure (GMFM) and its subsequent
revisions has become the most common functional outcome
measure used by rehabilitation specialists to measure motor
functioning in children with cerebral palsy and other neuro-
logical conditions (Alotaibi et al., 2014). For instance,
GMFM-66 was successfully used to evaluate children with
Leigh disease during EPI-743 treatment (Martinelli et al.,
2012). The baby is now 21 months old and, at neurological
examination, her attention, social interaction and cognitive
skills are notably improved, although a psychomotor delay
remains: the global quotient at Griffith Mental Scale corres-
ponds to 10 months of age. Both petechiae and acrocyan-
osis were also reduced. As shown in Fig. 1B and C, brain
MRI performed at 3 and 8 months after liver transplant
showed no further increase in basal ganglia lesions, which
appeared more defined, probably owing to scarring of pre-
existing necrotic areas. No new lesions were observed and the
reduction of subarachnoid spaces indicated markedly im-
proved trophism of the cortical ribbon. As seen in Fig. 2,
the last biochemical assessment showed complete and stable
normalization of plasma thiosulphate levels (3.2 mM, nv 54
mM) and marked decrease of urinary ethylmalonic acid
(69 mM/M creatine, nv 520) and of blood lactic acid (9–
43 mg/dl, nv = 6–22).
Discussion
Since its first description (Burlina et al.,1991,1994), more
than 80 patients, mainly originating from the Mediterranean
area or Arabic peninsula, have received a genetic diagnosis
of ethylmalonic encephalopathy. The natural history of the
disease has an invariably fatal course: onset is typically in
the first 2–4 months after birth, and is followed by
progressive clinical deterioration, usually leading to death
within the first years of life. All reported patients have ex-
hibited progressive clinical deterioration (Martinelli et al.,
2012) with psychomotor regression and complete absence
of neurological improvement. To the best of our knowledge,
the only exception is a single patient, who was compound
heterozygous for ETHE1 mutations and had a milder dis-
ease course, likely due to the maintenance of some residual
sulphur dioxygenase activity because of a hypomorphic
genotype (Pigeon et al.,2009). Opposite to the natural dis-
ease course, our patient, who presented a characteristic
severe phenotype, with psychomotor delay manifesting as
early as 5 months of age, clearly showed progressive im-
provement of neurological function after hepatic transplant,
as demonstrated by serial monitoring of functional scales.
Importantly, the number of necrotic lesions detected by
brain MRI has remained stable and cerebral atrophy has
improved, unlike the progressive worsening of the brain
MRI pattern generally observed in ethylmalonic encephalop-
athy. There are scarce literature data about the MRI follow-
up in ETHE1 patients; Grosso et al. (2002) described a
stable pattern of basal ganglia lesions in one patient, but
to our knowledge the improvement of cerebral atrophy
has not previously been described. Moreover, we also
observed improvement in skin microvascular damage with
reduction of petechial purpura and acrocyanosis. The clin-
ical improvement is strictly related to the amelioration of
biochemical parameters, since plasma thiosulphate levels,
which reflect toxic accumulation of the hydrogen sulphide
responsible for the disease phenotype, permanently
decreased to a normal range during the follow-up.
Liver transplantation has been attempted in other mito-
chondrial disorders where liver failure is the predominant
feature with variable success (De Greef et al., 2012;
Grabhorn et al., 2014;Hynynen et al., 2014). Among
other metabolic disorders, liver transplantation represents
a valid option in maple syrup urine disease and in urea
cycle defects, in which the defective metabolic pathways
are located mainly or exclusively in the liver, and in organic
acidurias (Ha
¨berle et al., 2012;Mazariegos et al., 2012;
Baumgartner et al., 2014;Yu et al., 2015). Liver trans-
plantation has significantly improved the long-term prog-
nosis in these disorders, which are all detectable by
newborn screening.
The successful use of liver transplantation in ethylmalo-
nic encephalopathy provides convincing proof of principle
that this novel therapeutic approach is effective in reverting
the natural history of an otherwise fatal neurological dis-
ease. This is particularly relevant as ethylmalonic enceph-
alopathy is diagnosable at birth by newborn screening,
offering the opportunity of an early liver transplant
(McHugh et al., 2011). Newborn screening can identify
C4 elevation in a dried blood spot; C4 elevation can be
found also in primary short-chain acyl-CoA dehydrogenase
(SCAD) deficiency (McHugh et al., 2011) and a precise
algorithm can be followed to distinguish between the two
disorders (https://www.acmg.net/StaticContent/ACT/
Liver transplant in ETHE1 disease BRAIN 2016: Page 5 of 7 |5
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Algorithms/Visio-C4.pdf). Although limited to a single case,
this report suggests that ethylmalonic encephalopathy
should be considered as a candidate disease for national
or state-mandated newborn screening, particularly in popu-
lations with relatively high frequencies of pathogenic al-
leles. Additionally, further work is needed to define the
spectrum of C4/C5 acylcarnitine elevations in proven
cases of ethylmalonic encephalopathy.
Importantly, our work strengthens the idea that the same
therapeutic approach could also be attempted in an another
mitochondrial disorder called MNGIE (mitochondrial neu-
rogastrointestinal encephalomyopathy), which shares a
somewhat similar pathogenic mechanism due to the accu-
mulation of toxic compounds such as thymidine and deox-
yuridine in plasma and tissues because of deficient
thymidine phosphorylase activity (Spinazzola et al., 2002).
The accumulation of nucleosides determines intramitochon-
drial deoxynucleotide pool imbalance with damage to mito-
chondrial DNA replication (Nishino et al., 1999), leading
to a slowly progressive deterioration of clinical conditions
with skeletal myopathy, peripheral neuropathy, gastrointes-
tinal dysmotility and cachexia.
In MNGIE, similar to ethylmalonic encephalopathy,
liver-targeted adeno-associated virus-mediated gene therapy
was proven to be successful in a murine model, therefore
liver transplantation could represent a valid therapeutic
option for this severe mitochondrial disorder (Boschetti
et al., 2014;Torres-Torronteras et al., 2014).
Supplementary material
Supplementary material is available at Brain online.
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