Case report

Respiratory chain
deficiency in a female
with Aicardi-Goutières
syndrome
Christine Barnérias MD;
Irina Giurgea MD, Department of Paediatrics;
Lucie Hertz-Pannier MD PhD, Paediatric Radiology Service;
Nadia Bahi-Buisson MD PhD, Department of Paediatrics;
Nathalie Boddaert MD PhD, Paediatric Radiology Service;
Pierre Rustin PhD;
Agnés Rotig PhD, INSERM U-393;
Isabelle Desguerre MD, Department of Paediatrics;
Arnold Munnich MD PhD, Department of Genetics and
INSERM U-393;
Pascale de Lonlay* MD PhD, Department of Paediatrics,
Hôpital Necker-Enfants Malades, Paris, France.
*Correspondence to last author at Service de Maladies
Métaboliques, Hôpital Necker-Enfants Malades,
149, rue de Sèvres 75743 Paris Cedex 15, France.
E-mail: pascale.delonlay@nck.aphp.fr

Aicardi-Goutières syndrome (AGS) is an early-onset
progressive encephalopathy characterized by calcifications of
the basal ganglia, white matter abnormalities, chronic
cerebrospinal fluid (CSF) lymphocytosis, and/or a raised level
α. We report a female with
of CSF interferon (INF)-α
mitochondrial respiratory chain deficiency fulfilling the
criteria of AGS. Disease onset was in the first year of age with
seizures and psychomotor regression. To date, at 4 years of
α in
age, she presents a severe encephalopathy, increased INF-α
the CSF, and calcifications of basal ganglia on computerized
tomography. Cerebral magnetic resonance imaging showed
bilateral and symmetric hypersignal of the posterior white
matter. A complex I deficiency of the mitochondrial
respiratory chain was found in skeletal muscle, which was
associated with a complex IV deficiency in cultured skin
fibroblasts. The question of whether this oxidative
phosphorylation deficiency is primary or secondary in AGS is
open to debate. We suggest giving consideration to systematic
evaluation of the mitochondrial respiratory chain in skeletal
muscle and skin fibroblasts of other AGS patients.

See end of paper for list of abbreviations.

Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous condition of hitherto unknown mechanism characterized by an early onset, progressive encephalopathy with
calcifications of basal ganglia, white matter abnormalities,
cerebrospinal fluid (CSF) lymphocytosis, and/or raised level
of CSF interferon (IFN)-α (Tolmie et al. 1995, McEntagart et
al. 1998). Here, we report on mitochondrial respiratory
chain deficiency in a child fulfilling the criteria of AGS.
Whether respiratory chain deficiency is primary or secondary
to cytokine abnormalities currently observed in AGS is still
questionable. Whatever the mechanism, it is of particular
interest to assess mitochondrial phosphorylation in other
AGS patients.
Case report
A female born to non-consanguineous parents after a term
pregnancy and normal delivery (birthweight: 3250g, length:
51cm, head circumference: 34cm) developed peripheral
hypertonia and axial hypotonia in the first year of life.
Generalized seizures uncontrolled by valproate first
occurred at the age of 16 months, followed by psychomotor
regression and failure to thrive (weight –2 SD, length –0.5
SD, head circumference –1.5 SD). Poor head control, poor
eye contact, and brisk tendon reflexes were noted at 20
months of age. Social responsiveness was present but poor.
Mild liver enlargement with elevated serum transaminases
was observed (4 × Normal). CSF proteins and white cell
count were normal (0.15g/l, 3 cells respectively). CSF lactate
(2.3mmol/l, normal below 2; CSF lactate/pyruvate ratio 24)

Developmental Medicine & Child Neurology 2006, 48: 227–230 227

and CSF INF-α were increased (6UI/l, normal range below 2).
Plasma amino acids and urinary organic acids were normal.
Electroretinogram, visual evoked potentials, and heart ultrasound were also normal. An elder brother presented with
learning disability*, cerebellar ataxia, and muscular weakness at the age of 10 years. Plasma levels of lactate and amino
acids and urinary organic acids were normal.

Method
Lactate, pyruvate, and ketone bodies were determined by the
enzymatic method and urinary organic acids by gas chromatograph. Deltoid muscle (120mg) was obtained under
local anaesthetic and mitochondria were prepared according to standard procedures. NADH ubiquinone reductase
*US usage: mental retardation.

a

b

Figure 1: Calcifications in basal ganglia (arrows), and cortico-subcortical
atrophy. (a) Axial magnetic resonance imaging, T1-weighted. (b) Computerized
tomography.

Figure 2: Bilateral hypersignals of the
white matter (arrows), particularly in
posterior regions (Coronal magnetic
resonance imaging, FLAIR).

Figure 3: MR spectroscopy
(Monovoxel, point-resolved
spectroscopy sequence, echo times
= 144ms) of basal ganglia shows
(a) slight decrease of N-acetyl
aspartate, (b) slight increase of
choline, and (c) a small peak of
lactate.

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Developmental Medicine & Child Neurology 2006, 48: 227–230

(NQR), fumarase, citrate synthase, lactate dehydrogenase,
cytochrome c oxidase (COX), and succinate cytochrome
reductase (SCCR) activities were spectrophotometrically measured according to Rustin et al. (1994). Polarographic studies
were performed as described previously (Rustin et al. 1994).
For histochemistry, the muscle specimen was immediately
frozen in liquid nitrogen-cooled isopentane and cross-serial
sections (10µ) were stained with hematoxylin-eosin, modified
Gomori trichrome, and different histochemical stains. Histochemical staining for COX was performed using a modified
method. Skin fibroblasts were grown in the medium RPMI
1640 (Gibco) supplemented with 10% foetal calf serum,
2mM glutamine, 2.5mM pyruvate, 200µM uridine, 100µg
streptomycin, and 100U/ml penicillin at 37˚C under standard conditions (Rustin et al. 1994). The screening for
mtDNA deletions and mutations was carried out as
described (Rustin et al. 1994).
Results
CT and T1-weighted magnetic resonance (MR) images of the
female at 2 years old showed calcifications of the basal ganglia,
ventricular dilatation, and cortical atrophy (Fig. 1). FLAIR MRI
showed bilateral and symmetric hyperintensities of the posterior white matter (Fig. 2). MR spectroscopy showed a small lactate peak in the basal ganglia (Fig. 3). The MRI of the elder
brother showed bilateral hypersignals of the white matter and
cerebellar hypoplasia.
Polarographic studies showed a low pyruvate oxidation in
skeletal muscle mitochondria-enriched fractions of the female
compared with controls (Table I). All activity ratios involving
complex I (e.g. pyruvate oxidation, NADH cytochrome c
reductase [NCCR] activity) were significantly abnormal and
consistent with a 50–60% deficiency of complex I in her skeletal muscle. Accordingly, spectrometric studies showed a 50%
decrease of complex I activity in her skeletal muscle biopsy
(Table I). A similar complex I deficiency was identified in cultured skin fibroblasts, which was moreover associated with a
decreased activity of complex IV (Table I). Histochemical
analysis of the skeletal muscle showed partial atrophy of type
II fibres and mild lipid vacuoles. COX histochemical staining
revealed a heterogeneously weak COX activity in a few muscle
fibres. A complex IV deficiency was identified in cultured skin
fibroblasts of the elder brother.
Neither large-scale rearrangement nor common mtDNA
mutations (A3243G, T10158C, T10191C, T12706C, G13513A,
A13514G, T14487C) were found in skeletal muscle.
Discussion
Here, we report on respiratory chain enzyme deficiency in a
patient fulfilling the criteria of AGS. The patient presented with
severe encephalopathy, liver enlargement, and elevated serum
transaminases. White cell count was normal but INF-α was
increased in the CSF. Calcifications of the basal ganglia were
noted on the CT and cerebral MRI showed bilateral and symmetric hypersignal of the posterior white matter abnormality.
Because clinical presentation of AGS was consistent with
the sequelae of a congenital infection, IFN-α was first
assessed and increased CSF IFN-α levels in the absence of
infection was consistent with AGS (Kuijpers 2002, Lebon et
al. 2002). This condition is genetically heterogeneous with
one locus (AGS1) on chromosome 3p21 (Crow 2002, Crow
et al. 2000). Two other conditions are clinically related to

AGS, namely Cree encephalitis and the pseudo-TORCH syndrome. Cree encephalitis differs from AGS by the presence of
systemic immune abnormalities with an apparent susceptibility to infections while pseudo-TORCH syndrome differs
from AGS by an early-onset microcephaly with neonatal liver
dysfunction, thrombocytopenia, and a normal white cell
count in the CSF (Crow et al. 2003). Yet, it is important to
remember that these features have been observed in several
patients diagnosed as AGS. For this reason, neither CSF
pleiocytosis nor elevated CSF IFN-α levels are regarded as
mandatory for diagnosis of AGS, particularly in late childhood. Our Azevedo-Martins (2003) patient fulfilled inclusion
criteria of AGS with liver disturbances.
The question of whether respiratory chain deficiency was
primary or secondary in our patient is open to debate. On the
other hand, mitochondrially-derived reactive oxygen species
are known to play a critical role in the activation of the
cytokine-sensitive transcription factor NF-KappaB. This could
denote a primary role for the oxidative phosphorylation
defect. Moreover, liver dysfunction as well as leukodystrophy
found in our patient are common findings in respiratory

Table I: Spectrophotometric analysis of mitochondrial
respiratory chain activities
Patient value

Muscle mitochondria
Activities (nmol/min/mg protein)
Pyruvate oxidase
8
Succinate oxidase
40
Duroquinol oxidase
51
NADH ubiquinol reductase
15
SCCR1
19
QCCR
682
COX
366
Activity ratios
Succ ox/pyr ox
5.3
DQ ox /succ ox
1.3
COX/NQR
41
COX/SCCR
2.7
COX/QCCR
0.47
Cultured fibroblasts
Activities (nmol/min/mg protein)
Pyruvate oxidase
7
Succinate oxidase
12
NADH ubiquinol reductase
15
SCCR
33
QCCR
84
COX
138
Activity ratios
DQ ox /succ ox
1.3
COX/NQR
9.5
COX/SCCR
4.1
COX/QCCR
0.3

Control values (n=80)
range; mean (SD)

19–51
31–93
51–145
39–100
112–367
500–1539
372–1240
1.9 (0.7)
1.7 (0.2)
10.8 (2.0)
3.2 (0.3)
0.50 (0.08)

7–11
10–21
16–35
29–57
64–107
191–344
1.7 (0.2)
10.4 (1.2)
6.3 (0.7)
0.6 (0.03)

Substrate oxidation was measured polarographically.
SCCR, succinate cytochrome c reductase (complex II and III);
QCCR, ubiquinol cytochrome c reductase (complex III); COX,
cytochrome c oxidase (complex IV); Succ, succinate; ox, oxidase;
pyr, pyruvate; DQ, duroquinol; NQR, NADH ubiquinone reductase
(complex I). Abnormal values are indicated in bold characters.

Case Report

229

chain deficiencies (Schuelke et al. 1999, de Lonlay-Debeney
et al. 2000). Conversely, respiratory chain deficiency could be
regarded as a secondary event in AGS, as cytokines are known
to down-regulate mitochondrial gene expression with a
reduction in cellular ATP levels (Lou et al. 1994, Lewis et al.
1996) and to mediate organ inflammation leading to mitochondrial dysfunction (Kaneda et al. 2003). Moreover, IFN-α
has been shown to depress mitochondrial respiration in
vitro, by depleting mitochondrial transcription factor A
(Inagaki et al. 1997). However, none of the genes involved in
cytokine pathways has been identified at the 3p23 locus.
Whatever the mechanisms of the oxidative phosphorylation defect, this observation should prompt the investigation
of oxidative phosphorylation in AGS and conversely the
assessment of CSF IFN-α in respiratory chain deficiency. We
suggest, therefore, that genetic disorders of the mitochondrial respiratory chain should be regarded as a possible cause
or consequence of AGS.
DOI: 10.1017/S001216220600048X
Accepted for publication 12th May 2005.
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List of abbreviations
AGS
ATP
COX
CSF
GC
INF-α
SCCR

Aicardi-Goutières syndrome
Adenosine triphosphate
Cytochrome c oxidase
Cerebrospinal fluid
Gas chromatography
Interferon alpha
Succinate cytochrome reductase

Erratum
‘Balancing certainty and uncertainty in clinical medicine’
Hayward
DMCN Vol 48: 74–77
We would like to correct an error that was printed in the above mentioned article:
p 77: The sentence should have read: ‘This article is based on Professor Hayward’s inaugural lecture as Professor of Paediatric
Neurosurgery, delivered at the Institute of Child Health...’ and not ‘This article is based on Professor Hayward’s inaugural lecture
as President of the Royal College of Paediatrics and Child Health at the Institute of Child Health...’
We sincerely apologize for this error.

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Developmental Medicine & Child Neurology 2006, 48: 227–230

DOI: 10.1017/S001216220600051X