POLG mutations and Alpers syndrome
ABSTRACT Alpers–Huttenlocher syndrome (AHS) an autosomal recessive hepatocerebral syndrome of early onset, has been associated with mitochondrial DNA (mtDNA) depletion and mutations in polymerase gamma gene (POLG). We have identified POLG mutations in four patients with hepatocerebral syndrome and mtDNA depletion in liver, who fulfilled criteria for AHS. All were compound heterozygous for the G848S and W748S mutations, previously reported in patients with progressive external ophtalmoplegia or ataxia. We conclude that AHS should be included in the clinical spectrum of mtDNA depletion and is often associated with POLG mutations, which can cause either multiple mtDNA deletions or mtDNA depletion. Ann Neurol 2005;57:921–924
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ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is not a single disease entity, rather it describes a spectrum of liver conditions that range from fatty liver (steatosis) to more severe steatosis coupled with marked inflammation and fibrosis (non-alcoholic steatohepatitis (NASH)) through to severe liver disease such as cirrhosis and possibly hepatocellular carcinoma. Obesity, notably abdominal obesity, is a common risk factor for NAFLD. The pathogenesis from steatosis to NASH is poorly understood and the “two hit” model, as suggested nearly two decades ago, provides a feasible starting point for characterisation of underlying mechanisms. This review will examine the oxidative stress factors (‘triggers’) which have been implicated as a “second hit” in the development of primary NASH. It is would be reasonable to assume that multiple, rather than single, pro-oxidative intracellular and extracellular triggers act in conjunction promoting oxidative stress that drives the development of NASH. It is likely that the common denominator of these pro-oxidative triggers is mitochondrial dysfunction. Understanding the contribution of each of these ‘triggers’ is an essential step in starting to understand and elucidate the mechanisms responsible for progression from steatosis to NASH, thus enabling the development of therapeutic targeting to prevent NASH development and progression. This article is protected by copyright. All rights reserved.Liver international: official journal of the International Association for the Study of the Liver 03/2014; · 4.41 Impact Factor
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ABSTRACT: Hepatic involvement is a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period. Respiratory chain disorders may present as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. In recent years, specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and the deletion or rearrangement of mitochondrial DNA) have been identified, with the promise of genetic and prenatal diagnosis. The current treatment of mitochondrial hepatopathies is largely ineffective, and the prognosis is generally poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease, which does not respond to transplantation. Prospective, longitudinal, multicentered studies will be needed to address the gaps in our knowledge in these rare liver diseases.The Journal of pediatrics 06/2013; · 4.02 Impact Factor
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ABSTRACT: Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity.Clinical biochemistry 06/2013; · 2.02 Impact Factor
detect the additionally analyzed mutations 3342A?G,
I1122V, and I2020T, the latter being the mutation
found in the Sagamihara family. Our results indicate
that these LRRK2 mutations are not a direct genetic risk
factor for sporadic PD in the Japanese population. It is
possible, however, that the gene product of LRRK2 plays
a key role, either causal or protective, in the pathogenesis
of sporadic PD in combination with other genetic or
This study was supported by the Japanese Ministry of Education,
Culture, Sports, Science and Technology (Grant-in-Aid for Scien-
tific Research 16015298 and 16590843, K.H.) and Kitasato Uni-
versity School of Allied Health Sciences (Grant-in-Aid for Research
Project 2004-01, F.O.).
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POLG Mutations and Alpers
Guido Davidzon, MD,1Michelangelo Mancuso, MD,1,2
Silvio Ferraris, MD,1Catarina Quinzii, MD,1
Michio Hirano, MD,1Heidi L. Peters, MD,3
Denise Kirby, PhD,3David R. Thorburn, PhD,3
and Salvatore DiMauro, MD1
Alpers–Huttenlocher syndrome (AHS) an autosomal re-
cessive hepatocerebral syndrome of early onset, has been
associated with mitochondrial DNA (mtDNA) depletion
and mutations in polymerase gamma gene (POLG). We
have identified POLG mutations in four patients with
hepatocerebral syndrome and mtDNA depletion in liver,
who fulfilled criteria for AHS. All were compound het-
erozygous for the G848S and W748S mutations, previ-
ously reported in patients with progressive external oph-
talmoplegia or ataxia. We conclude that AHS should be
included in the clinical spectrum of mtDNA depletion
and is often associated with POLG mutations, which can
cause either multiple mtDNA deletions or mtDNA deple-
Ann Neurol 2005;57:921–924
Alpers–Huttenlocher syndrome (AHS; progressive in-
fantile poliodystrophy) is an autosomal recessive hepa-
tocerebral syndrome. The typical course of AHS in-
cludes severe developmental delay, intractable seizures,
liver failure, and death in childhood.1,2Refractory sei-
zures, cortical blindness, progressive liver dysfunction,
and acute liver failure after exposure to valproic acid
are considered diagnostic features.3,4The neuropatho-
logical hallmarks of AHS are neuronal loss, spongiform
degeneration, and astrocytosis of the visual cortex.
Liver biopsy results show steatosis, often progressing to
Morphological and biochemical studies had sug-
gested involvement of the mitochondrial respiratory
chain in AHS.6–8A point mutation in the mtDNA
gene-encoding subunit II of cytochrome c oxidase
From the1Department of Neurology, Columbia University College
of Physicians and Surgeons, New York, NY;2Department of Neu-
rosciences, Neurological Institute, University of Pisa, Pisa, Italy;
3Murdoch Childrens Research Institute and Genetic Health Ser-
vices, Victoria Royal Children’s Hospital; and Department of Pae-
diatrics, University of Melbourne, Melbourne, Australia.
Received Sep 8, 2004, and in revised form Mar 2, 2005. Accepted
for publication Mar 13, 2005.
(www.interscience.wiley.com). DOI: 10.1002/ana.20498
Address correspondence to Dr DiMauro, 4-420 College of Physi-
cians and Surgeons, 630 West 168th Street, New York, NY 10032.
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
(COX II) was documented in a Finnish girl.9In two
siblings from one family, Naviaux et al documented
mtDNA depletion and decreased POLG activity,10and
recently reported mutations in the POLG gene both in
these patients and in a third unrelated child.5These
findings were confirmed in eight European patients
with AHS,11and we now report four more unrelated
children with hepatocerebral syndrome, mtDNA liver
depletion, and pathogenic POLG mutations.
Patients and Methods
We studied four children with hepatocerebral syndrome:
clinical and laboratory features, liver biopsy abnormalities,
and POLG mutations are summarized in the Table. All pa-
tients fulfilled diagnostic criteria for AHS in that they had
developmental delay, seizures, and hepatopathy leading to
liver failure. Age at death varied from 11 months to 8 years.
Lactic acidosis was present in three patients. Seizures were
difficult to control: status epilepticus occurred in three chil-
dren, and one had epilepsia partialis continua. Liver biopsy
typically showed centrilobular necrosis, regenerative nodules,
fibrosis, and both macro- and microvesicular steatosis. De-
tailed neuropathological evaluation was available only in pa-
tient 3: there was diffuse neuronal loss, gliosis, and spongi-
form change, especially in the occipital cortex; in patient 4,
the brain appeared normal despite clinical signs of encepha-
lopathy. In another child (patient 1), MRI of the brain
showed diffuse atrophy. Muscle biopsies or postmortem ex-
amination of muscle showed no abnormalities. The initial
diagnosis in most patients was cerebral palsy, before liver in-
sufficiency became apparent. Family history was noncontrib-
Enzyme and DNA Analysis
Respiratory chain enzymes in liver and muscle biopsies were
assayed as described previously.12Total DNA from patients’
muscle was extracted using standard protocols.
Real-time quantitative PCR was used to evaluate the
mtDNA content in liver. Both POLG and dGK were
screened by direct sequencing.14,15
Real-time PCR of liver biopsies from our patients (no
more liver tissue was available from patient 4) showed
mtDNA depletion, varying in severity from 87% to
94% (Table). Accordingly, the activities of respiratory
mtDNA were decreased in all liver extracts: mean re-
sidual activities for the four patients were 25% for
complex I; 31% for complex III; and 52% for complex
IV. In contrast, the mean activity of complex II, which
is entirely encoded by nuclear DNA, was 103% and
the mitochondrial marker citrate synthase was 267%.
None of the patients harbored dGK mutations. All
four patients were compound heterozygous for two
previously reported missense mutations, G2824A in
exon 16 (converting a glycine to a serine at amino acid
position 848) and G2525C in exon 13 (converting a
tryptophan to a serine at position 748) (Table). In ad-
dition, all of the patients harbored a heterozygous
single-nucleotide polymorphism (A3710G in exon 21,
converting a glutamate to a glycine at position 1143),
which is also present in about 3%–5% of the control
Our study reinforces the concepts that AHS is one
clinical phenotype associated with mitochondrial deple-
tion, and that POLG mutations can cause both
MtDNA depletion and AHS. In patients with mtDNA
depletion affected tissues have markedly reduced
mtDNA copy numbers, which result in impaired syn-
thesis of all respiratory chain components containing
mtDNA-encoded subunits. MtDNA depletion can be
tissue specific or multisystemic and is inherited as an
autosomal recessive trait. Mutations in the deox-
yguanosine kinase (dGK) gene have been associated
with the hepatocerebral form,15,16and changes in the
thymidine kinase 2 (TK2) gene with the myopathic
Mutations in POLG cause heterogeneous and usually
severe clinical phenotypes typically associated with ei-
ther autosomal dominant or recessive progressive exter-
nal ophthalmoplegia (PEO). In addition to PEO, com-
mon manifestations of POLG mutations include
neuropathy, ataxia, hypogonadism, migraine, hearing
loss, muscle weakness, parkinsonism, and psychiatric
symptoms.19A predominantly ataxic syndrome with-
out PEO has also been described.20The association of
deficient POLG activity and of POLG mutations with
AHS was first recognized by Naviaux and col-
leagues5,10in two unrelated American families and re-
cently confirmed by Ferrari and coworkers in eight Eu-
ropean patients.11We have further established the
etiological role of POLG mutations in five Australian
children with AHS. Both mutations that we identified
in these patients had been previously described. The
G848S mutation—in compound heterozygosity—had
been reported in patients with PEO,19and the W748S
mutation in patients with ataxia without PEO;20they
were also present in three of the European AHS cases.
These mutations result in the substitution of highly
conserved amino acids, one (G848S) located within
polymerase motif C of the enzyme, the other (W748S)
within a block of six amino acids forming a ?-sheet in
the spacer region of the enzyme.20The coexistence of
the W748S mutation with the E1143G polymorphism
in all four of our AHS patients, two European pa-
tients,11and three patients described by Van Goet-
hem18may be due to a founder effect. However, the
contribution of the E1143G polymorphism to the phe-
notype—if any—remains unclear.
Annals of NeurologyVol 57No 6June 2005
Interestingly, the G848S mutation, in compound
heterozygosity with a T251I transition, had been found
in a family with autosomal recessive progressive exter-
nal ophthalmoplegia and multiple mtDNA deletions in
muscle.15Patient 5 is the European series harbored the
G848S mutation in compound heterozygosity with an
A467T substitution, and four Alpers patients with the
G848S mutation also had the W748S substitution. It
is not clear how the same mutation can be associated
with either multiple deletions or depletion of mtDNA.
Threonine 251 is close to the Exo II motif of POLG,
whereas tryptophan 748 is part of a spacer region.
Thus, it appears that G848S acts as a recessive muta-
tion, and its effect on mtDNA stability or replication
depends on the associated mutation.
Although based on a small series of patients, our
data confirm that POLG mutations cause AHS thus
expanding the spectrum of clinical presentations asso-
ciated with mutations in this gene.
This study was supported by the NIH (National Institute for Neu-
rological Disorders and Stroke, NS11766, and National Institute of
Child Health and Human Development, HD32062), the Muscular
Dystrophy Association, and the Marriott Mitochondrial Disorder
Clinical Research Fund (MMDCRF).
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Table. Clinical Features, Liver Pathology, and POLG Mutations in Four Children with Alpers Syndrome
Depletion POLG Mutations
S ? status epilepticus; EPC ? epilepsia partialis continua; M ? myoclonic epilepsy; B ? blood; CSF ? cerebrospinal fluid; U ? urine; F ?
fibrosis; MVS ? microvesicular steatosis; nd ? not determined.
Mancuso et al: POLG Mutations and AHS