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Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia.

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Antioxidant Treatment Improves In Vivo
Cardiac and Skeletal Muscle Bioenergetics in
Patients with Friedreich’s Ataxia
Raffaele Lodi, MD,1,2 Paul E. Hart, MRCP,3 Bheeshma Rajagopalan, MD,1 Doris J. Taylor, DPhil,1
Jenifer G. Crilley, MD,1 Jane L. Bradley, PhD,3 Andrew M. Blamire, PhD,1
David Manners, BsC,1 Peter Styles, DPhil, Anthony H.V. Schapira, MD,3,4 and J. Mark Cooper, PhD3
Friedreich’s ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated
with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a
mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin
deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated
production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) has confirmed the deficits of respiratory chain complexes in these
tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase
activities in cardiac muscle. We used 31P-MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme
Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only
3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% ( p ⴝ 0.03)
and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% ( p ⴝ 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of
patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic
evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal
of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a
disease-modifying strategy in this neurodegenerative disorder.
Ann Neurol 2001;49:590 –596
Friedreich’s ataxia (FA), the most common form (frequency 1:30 –50,000) of the inherited ataxias, is an autosomal recessive degenerative disorder, characterised
clinically by onset before the age of 25 years of progressive gait and limb ataxia, absence of deep tendon
reflexes and extensor plantar responses, and loss of position and vibration sense in the lower limbs.1 Cardiomyopathy is often present in FA patients.2 The disease
is caused in most cases by a GAA repeat expansion in
the first intron of the FA gene (chromosome 9),3
which results in deficiency of a mitochondrial protein
called frataxin.4 – 6 Although frataxin function is still
unknown, from the yeast YFH1 model of the disease
there is evidence that deficiency of the yeast frataxin
homolog leads to a severe defect of mitochondrial respiration, loss of mitochondrial DNA, intramitochon-
drial iron accumulation, and increased sensitivity to oxidative stress.5– 8
Clues provided by the YFH1 knockout yeast strain
have been proved to be relevant to the pathogenesis of
FA as shown by recent investigations in patients. Studies performed on cardiac muscle samples from FA patients collected by biopsy or at postmortem have
shown reduced activities of respiratory chain complexes
I, II, and III and aconitase and increased cardiac iron
deposition.9 –11 Although the role of frataxin is still not
known, these enzymes all contain iron-sulphur (Fe-S)
clusters, so frataxin could play a role in mitochondrial
iron metabolism and the formation of Fe-S centres, or,
alternatively, these enzymes may be targeted because of
their particular sensitivity to damage by oxygen free
radicals.10 Moreover, support for defective mitochon-
From the 1MRC Biochemical and Clinical Magnetic Resonance
Unit, Department of Biochemistry, University of Oxford and Oxford Radcliffe Hospital, Oxford, United Kingdom; 2Dipartimento
di Medicina Clinica e Biotecnologia Applicata, Universita di Bologna,
Bologna, Italy; and 3University Department of Clinical Neurosciences, Royal Free and University College Medical School, and 4Institute of Neurology, University College, London, United Kingdom.
Published online 2 April 2001.
Received Jan 6, 2000, and in revised form Oct 4, 2000. Accepted
for publication Nov 10, 2000.
590
© 2001 Wiley-Liss, Inc.
Address correspondence to Dr Lodi, MD, PhD, Dipartimento di
Medicina Clinica e Biotecnologia Applicata “D. Campanacci,” Universita di Bologna, Policlinico S. Orsola, Via Massareti 9, 40138
Bologna, Italy. E-mail: lodi@med.unibo.it
drial oxidative phosphorylation in FA patients comes
from our recent demonstration that phosphorus magnetic resonance spectroscopy (31P-MRS) can detect in
vivo defects of cardiac12 and skeletal13 muscle energy
metabolism in FA patients.
Currently there is no established treatment for FA.
However, the biochemical defects observed to date in
FA suggest that the mitochondrial respiration deficit
may be amenable to treatment with antioxidants. To
test this hypothesis, we performed a study in 10 FA
patients who were given Coenzyme Q10 (CoQ10; 400
mg/day) and vitamin E (Vit E; 2,100 IU/day) as antioxidant therapy. The effect of such treatment on FA
patients’ cardiac and skeletal muscle energy metabolism
was assessed in vivo by means of 31P-MRS performed
before and after 3 and 6 months of therapy.
Subjects and Methods
Subjects
Ten FA patients (5 males, age range 16 – 40 years, mean ⫾
SD 28 ⫾ 6 years), 10 healthy volunteers for the calf (5
males, age range 22– 41 years, mean ⫾ SD 28 ⫾ 5 years)
and 10 different healthy volunteers for the cardiac muscle
31
P-MRS (5 males, age range 16 – 40 years, mean ⫾ SD
28 ⫾ 6 years) were studied. The diagnosis of FA was confirmed by detection of a GAA repeat expansion in the first
intron of both alleles of the frataxin gene using methods previously described.11 The GAA expansions were in the range
290 to 900 repeats for the shorter of the two alleles. FA
patients were assessed neurologically before and after 6
months of therapy using the semiquantitative International
Cooperative Ataxia Rating Scale (ICARS),14 which can be
subdivided into kinetic, gait and posture, speech, and ocular
categories. On this scale of 0 to 100, higher scores imply
more severe disease. Informed consent was obtained from
each patient and normal volunteer, and studies were carried
out with approval of the Central Oxford and Royal Free
Hospital Ethics Committees.
Echocardiography
2D- and M-mode imaging from parasternal and apical windows was performed before and after 3 and 6 months of
therapy using Sonos-5500 (Hewlett Packard, Bracknell,
United Kingdom). Images were recorded on optical disk for
subsequent analysis. Standard M-mode measurements were
made using established criteria.15 Left ventricular (LV) mass
index (LVMi) was derived from the M-mode measurements
using the Wikstrand formula and adjusted for height. Ejection fraction (EF) was calculated from LV volumes (derived
using modified Simpson’s rule).
Magnetic Resonance Spectroscopy
31
P-MRS studies were performed in a 2.0 T whole-body
magnet (Oxford Magnet Technology, Oxon, United Kingdom) interfaced to a Bruker Avance spectrometer (Bruker
Medical GmbH, Ettlingen, Germany). Skeletal muscle 31PMRS spectra were obtained from the right calf muscle at
rest, during an aerobic incremental exercise of plantar flex-
ion, and in the following recovery period as previously described.13 Relative concentrations of inorganic phosphate
(Pi), phosphocreatine (PCr), and adenosine triphosphate
(ATP) were obtained by a time-domain fitting routine16 using the AMARES algorithm and MRUI software17,18 and
were corrected for magnetic saturation. Absolute concentrations were obtained by assuming that the concentration of
ATP in normal muscle is 8.2 mM (ie, mmol/litre of intracellular water).13 Free [ADP] was calculated from the creatine kinase equilibrium.13 PCr recovery half-times were calculated from the slope of semilogarithmic plots19 using the
end-exercise and the first 3 recovery spectra. Initial rates of
PCr resynthesis after exercise, V (mM/min), were calculated
from the exponential rate constant of PCr recovery (k ⫽
0.693/t1/2) and the total fall in [PCr] during exercise
(⌬[PCr]) as V ⫽ k. ⌬[PCr].19 Using the hyperbolic ADP
control model for mitochondrial respiration and a normal
Km for ADP of 30 ␮M,19 we calculated the maximum rate
of mitochondrial ATP synthesis (Vmax) from the initial rate
of PCr postexercise resynthesis (V) and the end-exercise
[ADP] ([ADP]end): Vmax ⫽ V[1 ⫹ (Km/[ADP]end)].19
For the cardiac muscle studies, patients were positioned
prone, and standard multislice spin-echo images (TR ⫽
heart rate, TE ⫽ 25 msec, slice ⫽ 10 mm, 5 slices) were
acquired using a double rectangular surface coil placed
around the chest to confirm subject placement in the magnet
and to guide spectral localisation. After shimming was performed (using a 15-cm-diameter circular 1H surface coil centred beneath the heart), the coil system was exchanged for an
8-cm-diameter circular 31P surface coil. Cardiac spectra were
acquired using a one-dimensional chemical shift imaging
(1D CSI) sequence to encode signals with depth into the
chest.20 Spectral localisation was improved by using presaturation bands positioned over the chest wall using the proton
images.21 Cardiac signal was acquired from an 8-cm-thick
axial slice (again guided by the proton images) and phaseencoded to provide spectra from 1-cm-thick coronal slabs
through the heart. All proton and phosphorus data acquisition was cardiac-gated from a pulse oximeter probe placed
on a finger. Saturation correction factors for PCr and ATP
were measured by obtaining 1D CSI spectra from phosphate
phantoms of known T1 at different repetition rates. The
pulse angle at the surface of the coil was similar for equivalent power levels whether the load was a phantom or a human subject. T1s of PCr and ATP were assumed to be 4.3
seconds and 2.52 seconds, respectively, these values being the
average of published data.20 The proton images were used to
determine the location of spectra in the cardiac 1D CSI data
set arising from the myocardium. Typically, composite cardiac 31P spectra were obtained by adding 2 or 3 1D CSI
rows collected from the apex and part of the septum and the
posterior wall. Spectra were then fitted using a purposewritten interactive frequency domain-fitting program.21
Time domain signals were simulated for PCr, the 3 peaks of
ATP, PDE, and 2,3-DPG incorporating prior knowledge of
peak chemical shifts and j-couplings. Each signal component
was simulated allowing for missing initial data points (because of the phase-encoding duration of the acquisition experiment). Signal amplitude and exponential decay of each
component were adjustable, and a Gaussian decay could also
be applied to the entire free induction decay (FID). The sim-
Lodi et al: Antioxidant Therapy in Friedreich’s Ataxia
591
was reduced in FA patients (1.34 ⫾ 0.59, n ⫽ 9) compared to controls (2.40 ⫾ 0.14, p ⫽ 0.0003; Table 1),
as shown previously.12 After 3 months of CoQ10 and
Vit E therapy, the cardiac PCr/ATP in the 9 FA patients was significantly increased (2.02 ⫾ 0.42, p ⫽
0.03 relative to pretherapy values), and this improvement was sustained after 6 months of therapy (2.02 ⫾
0.43, p ⫽ 0.03 relative to pretherapy values; Table 1,
Fig 2). Cardiac PCr/ATP did not increase in patients 9
and 10, both with left ventricular hypertrophy (LVH),
but it should be noted that patient 9 was the only patient with normal cardiac PCr/ATP before therapy.
The extent of cardiac PCr/ATP increase after therapy
was independent of the patients’ GAA repeat length
(data not shown). In general there was a greater degree
of PCr/ATP recovery in the 4 FA patients without
LVH than in the 5 patients with LVH (Table 1). In
fact, although before treatment the mean PCr/ATP ratio in the 4 FA patients with no LVH was lower
(1.24 ⫾ 0.57) than in those with LVH (1.42 ⫾ 0.61),
after 3 months of CoQ10 and Vit E administration,
PCr/ATP was higher in patients without (2.30 ⫾ 0.30)
than in those with (1.79 ⫾ 0.38) hypertrophy, which
was confirmed at 6 months.
The rate of skeletal muscle oxidative metabolism is
conveniently assessed in vivo by stimulating mitochondrial respiration with an in-magnet exercise protocol.
As was shown previously,13 the skeletal muscle maximum rate of mitochondrial ATP synthesis (Vmax), calculated from the initial rate of PCr recovery and the
end-exercise [ADP],19 was severely reduced in FA pa-
ulated FID was Fourier-transformed and compared to the
actual spectrum and root mean square residuals calculated as
a measure of the fit. After fitting, the ATP signal was corrected for blood contamination based on the amplitude of
the 2,3-DPG22 and the final PCr/ATP ratio was calculated.
Statistical Analysis
Individual results were taken as abnormal when they fell outside the normal range. In view of the low number of subjects, nonparametric tests were used. The Mann-Whitney
U-test was used to compare independent groups and the
Wilcoxon’s matched pair test to compare dependent groups
(ie, data collected from FA patients before and during therapy). Statistical significance was taken as p ⬍ 0.05. Correlation coefficients were calculated by linear regression.
Results
CoQ10 and Vit E administration was well tolerated by
all patients and did not cause noticeable side effects.
The 31P-MRS and echocardiography results are shown
in Table 1 and Figures 1 and 2, and the patient details
and neurological evaluations are shown in Table 2. Patient 5 was in asymptomatic atrial fibrillation at the 3
and 6 month study points, so cardiac 31P-MRS was
not performed and his cardiac data were excluded from
the pre- and posttreatment cardiac 31P-MRS evaluation. After baseline 31P-MRS studies, patient 7 received
botulinum toxin injections in both calves to alleviate
severe spasticity, and, in view of the chemical denervation caused by the toxin, her skeletal muscle pre- and
posttreatment results were not included in the study.
Before therapy the mean cardiac PCr/ATP, which is
a measure of the energetic state of cardiac muscle,23,24
Table 1. Patient Details, Cardiac and Skeletal Muscle
(M) of Antioxidant Treatmenta
Cardiac
31
31
P-MRS Data, and Echocardiography Before and after 3 and 6 Months
P-MRS
Skeletal Muscle
PCr/ATP
Patient
1
2
3
4
5
6
7
8
9
10
Mean
SD
Normal
27/F
27/F
32/F
40/F
28/M
16/M
25/F
26/M
26/M
32/M
27.9
6.1
GAA
Repeat
Number
Disease
Duration
(Years) Baseline
3
M
(%)
6
M
(%)
390
590
290
450
650
900
460
630
620
400
538
176
⬎40
11
7
12
20
14
4
6
10
2
14
10.0
5.4
148
128
305
283
–
266
187
109
88
89
178
86
137
111
281
265
–
355
194
114
92
82
181
98
1.84
1.62
0.77
0.74
–
0.68
1.21
1.33
2.35
1.55
1.34
0.56
⬎2.20
Echocardiography
P-MRS
Vmax
CoQ10/Vit E
Age/Sex
(Years)
31
IVSd
CoQ10/Vit E
Baseline
(mM/min)
20.0
27.3
29.9
23.7
14.4
11.6
–
19.9
15.6
16.3
19.8
6.14
⬎37
3
M
(%)
6
M
(%)
170
102
89
138
133
247
–
118
127
124
139
47
149
105
82
170
170
255
–
128
116
108
143
52
PWd
CoQ10/Vit E
Baseline
(cm)
0.98
1.07
1.00
0.90
1.00
1.70
1.10
1.00
1.10
1.26
1.11
0.23
⬍1.10
3
M
(%)
6
M
(%)
76
75
93
116
106
73
102
131
102
109
98
19
87
87
91
120
104
83
92
134
77
101
98
18
CoQ10/Vit E
Baseline
(cm)
1.09
0.70
0.90
1.00
1.00
1.24
1.20
1.20
1.10
1.59
1.10
0.24
⬍1.10
3
M
(%)
6
M
(%)
64
131
94
92
106
119
97
111
98
87
100
18
74
141
93
93
116
108
88
113
95
87
101
19
IVSd and PWd baseline values in cm; % ⫽ 3 or 6 month treatment examination as a percentage of the baseline value; PCr ⫽ phosphocreatine; Vmax ⫽
maximum rate of mitochondrial adenosine triphosphate (ATP) production.
a
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Annals of Neurology
Vol 49
No 5
May 2001
Fig 1. 31P-MRS cardiac spectra from control and Friedreich’s
ataxia (FA) cases 3 and 4 before and after 3 months of
CoQ10 plus Vit E therapy. The phosphocreatine (PCr) peak
[relative to adenosine triphosphate (ATP)] is reduced in the
pretreatment spectra of the two FA patients compared to the
control spectrum. After 3 months of antioxidant therapy, the
PCr peak increases in both patients compared to the pretherapy levels. 2,3 DPG ⫽ 2,3-diphosphoglycerate; ␥, ␣, and
␤ ⫽ the three phosphate groups of ATP.
tients (19.8 ⫾ 6.1 mM/min, n ⫽ 9) compared to controls (57.8 ⫾ 19.0, p ⫽ 0.0001; Table 1, Fig 2). After
3 and 6 months of CoQ10 and Vit E treatment, mitochondrial Vmax increased to 25.8 ⫾ 5.5 ( p ⫽ 0.01)
and 26.5 ⫾ 6.7 ( p ⫽ 0.02), respectively, in the 9 FA
patients (Table 1, Fig 2). It can be seen in Table 1 that
only patients 2 and 3 did not show any improvement
in their Vmax. The extent of muscle Vmax increase after
therapy was higher in patients with longer GAA repeat
length (r ⫽ 0.63, p ⫽ 0.06 after 3 months of therapy;
r ⫽ 0.71, p ⫽ 0.03 after 6 months of therapy).
The echocardiographic analyses performed before
therapy indicated that 5 patients (patients 6 –10; Table
1) showed LVH as defined on the basis of a posterior
wall (PWd) and/or septal (IVSd) thickness ⱖ1.1 cm in
diastole (1.27 ⫾ 0.19 and 1.23 ⫾ 0.28, respectively),
whereas in the other 5 patients (patients 1–5; Table 1)
Fig 2. Cardiac phosphocreatine to adenosine triphosphate ratio
(PCr/ATP; A) and calf muscle maximum rate of mitochondrial ATP production (Vmax; B) in controls and in an Friedreich’s ataxia (FA) patient before (0M) and after 3 months
(3M) and 6 months (6M) of CoQ10 plus Vit E therapy.
PWd and IVSd thickness were ⬍ 1.1 cm (0.94 ⫾ 0.15
and 0.99 ⫾ 0.06, respectively). After 3 months of therapy, PWd and IVSd thickness were unchanged both in
patients with LVH (1.29 ⫾ 0.16, p ⫽ 0.8; 1.23 ⫾
0.11, p ⫽ 0.5, respectively) and in patients without
LVH (0.89 ⫾ 0.13, p ⫽ 0.6; 0.91 ⫾ 0.14, p ⫽ 0.3,
respectively). LVMi was unchanged before and after
therapy in patients with LVH (40 ⫾ 12 vs 46 ⫾ 8
g/m, p ⫽ 0.6) and in patients without LVH (34 ⫾ 8
vs 34 ⫾10 g/m, p ⫽ 0.5). Similarly, fractional shortening (FS) was unchanged after therapy in FA patients
either with (36% ⫾ 3% vs 38% ⫾ 9%, p ⫽ 0.6) or
without (34% ⫾ 10% vs 35% ⫾ 7%, p ⫽ 0.6) LVH.
These findings were confirmed after 6 months of therapy (Table 2).
The ICARS score14 increased in 6 of the patients
and just failed to reach statistical significance ( p ⫽
0.06) after 6 months of therapy. Patients 2, 6, and 8
showed the most marked deterioration in their clinical
scores, which reflected a marked increase in the kinetic
Lodi et al: Antioxidant Therapy in Friedreich’s Ataxia
593
Table 2. Neurological Evaluation of Friedreich’s Ataxia Patients at Baseline and after 6 Months (M) of Therapy (Maximum
Possible Scores in Parentheses)
International Cooperative Ataxia Ratings Scalea
Posture and Gait
(34)
Kinetic (52)
Speech (8)
Oculomotor (6)
Total (100)
Patient
Baseline
CoQ10/Vit
E (6 M)
Baseline
CoQ10/Vit
E (6 M)
Baseline
CoQ10/Vit
E (6 M)
Baseline
CoQ10/Vit
E (6 M)
Baseline
CoQ10/Vit
E (6 M)
1
2
3
4
5
6
7
8
9
10
Mean
SD
25
23
11
22
32
24
24
27
11
11
21.0
7.4
27
29
10
24
31
27
29
28
13
14
23.2b
7.8
23
27
12
30
29
15
27
20
22
31
23.6
6.4
23
27
13
30
31
25
27
26
21
26
24.9
5.1
2
3
2
5
4
2
4
4
4
3
3.3
1.1
2
3
2
4
4
2
4
4
2
3
3.0
0.9
3
1
1
4
4
3
3
2
1
3
2.5
1.2
3
2
2
3
3
2
1
2
2
3
2.3
0.7
53
54
26
61
69
44
58
53
38
48
50.4
12.2
55
61
27
61
69
56
61
60
38
46
53.4
12.7
a
b
J. Neurol. Sci. 1997;145:L05–L11.
P ⬍ 0.05.
score in 2 cases (patient 6 and 8) and an increase in the
posture and gait score of the third (patient 2). The
breakdown of the scores into posture and gait, kinetic,
speech, and ocular categories indicated that there were
no marked changes in these categories; however, the
posture and gait scores deteriorated in 8 of the patients, which reached statistical significance ( p ⫽ 0.02;
Table 2). Hand clicker scores were not significantly
different between baseline and 6 month values for either the right (75 ⫾ 13 and 78 ⫾ 16 clicks in 30 sec,
p ⫽ 0.2) or the left (65.1 ⫾ 13.1 and 63 ⫾ 14.5 clicks
in 30 sec, p ⫽ 0.2) hand.
Discussion
We report here for the first time that antioxidant therapy based on oral CoQ10 and Vit E administration can
improve cellular bioenergetics in FA, as measured directly and in vivo in cardiac and skeletal muscle. The
duration of our study was relatively short, and a longer
period may be required to show whether 31P-MRS
bioenergetic indices improve in all FA patients.
The Vit E and CoQ10 doses used in our study were
similar to those administered to patients with other
neurodegenerative disorders for which no side effects
were reported.25,26 Both drugs localise to cellular membranes, including mitochondrial membranes, and act as
free radical scavengers in addition to the role of CoQ10
in electron transfer. We combined the two antioxidants
to amplify their efficacy. Vit E has been shown in vitro
to reduce the formation of the ubisemiquinone-10 radical, thus increasing the lipophilicity of CoQ1027; on
the other hand, CoQ10 is necessary for the regeneration of ␣-tocopherol from its phenoxyl radical.28
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Annals of Neurology
Vol 49
No 5
May 2001
Many FA patients have echocardiographic evidence
of cardiomyopathy, including LVH.2 This may be a
reflection of the relatively high cardiac expression of
frataxin3 and of the low antioxidant defences of cardiac
tissue,29 which may also explain the more severe mitochondrial abnormalities in FA heart compared to skeletal muscle.11 The more marked bioenergetic improvement after therapy that we found in cardiac compared
to skeletal muscle may reflect a greater dependence on
frataxin and greater accumulation of iron and free radical mitochondrial damage in the FA heart. We have
previously shown that a profound reduction in the
PCr/ATP ratio is also present in FA patients without
LVH, which led us to hypothesise that LVH in FA
may be a direct effect of the cardiac energy metabolism
deficit.12 The greater degree of PCr/ATP improvement
in the 4 FA patients without LVH than in the 5 patients with LVH may indicate that the presence of
LVH reduces the rate of bioenergetic recovery and that
antioxidant treatment may be more effective when
started before cardiomyopathy becomes established. Indeed, if the bioenergetic deficit precedes cardiac hypertrophy, the early initiation of antioxidant therapy in
FA patients may prevent the development of cardiac
hypertrophy by reversing the bioenergetic abnormality.
Despite these bioenergetic improvements, echocardiography after 3 and 6 months of therapy failed to identify a consistent reduction in LVMi, PWd, or IVSd,
even in the subgroup of patients with LVH. Although
8 of the 10 patients showed decreases in either the
PWd or the IVSd thickness, these changes were not
statistically significant and were within the reproducibility error of the echocardiography technique. It is
possible that a longer period of therapy would be required to achieve significant regression of LVH. A preliminary report showed a decrease in lVSd, PWd, and
LVMi in 3 FA patients treated for 4 –9 months with
idebenone, a short-chain quinone analogue that acts as
a powerful free radical scavenger.30
In skeletal muscle, the increase in the Vmax correlated positively with the number of GAA repeats in the
smaller allele: The higher the number of repeats, the
higher the relative improvement after therapy. As was
previously shown,13 the degree of deficit of skeletal
muscle bioenergetics is more severe in FA patients with
higher GAA repeat number, and skeletal muscle bioenergetics of these patients may benefit relatively more
from CoQ10/Vit E therapy. On the other hand, cardiac
PCr/ATP levels did not relate to the length of GAA
repeats,12 and relative improvement in PCr/ATP after
therapy was also not correlated with GAA repeat
length.
The improved MRS findings in the cardiac and calf
muscles in FA patients after 3 and 6 months of therapy
confirm the potential benefits of this therapy to the
energy supply to the heart and skeletal muscles. If these
benefits extrapolate to the other cells in the body, in
particular nerve cells, it might be hoped that the improvement in cell function and prevention of cell death
would contribute to a slowing of the progression of the
disease and possibly to some improvements in symptoms. After 6 months of therapy, we failed to detect
improvements in the ICARS score in the 10 FA patients. The evaluation of the clinical efficacy of a new
therapy in progressive degenerative disorders such as
FA is particularly difficult in that it is complicated by
many factors, not least the fact that the neurological
symptoms associated with FA are predominantly due
to neuronal loss. This study was designed as a pilot to
test whether combined CoQ10 plus Vit E therapy
could improve tissue bioenergetics in FA patients and
thereby promote trials oriented to evaluation of the
clinical response to such a therapy. Extension of the
therapy regime will help to determine whether the clinical symptoms are affected. However, both improved
clinical tests and a larger controlled trial will be required to evaluate the efficacy of treatment on disease
progression.
In conclusion, our in vivo observations suggest that
antioxidant therapy may be of clinical benefit to FA
patients. The dramatic improvement of cardiac and
skeletal muscle bioenergetics was detectable after only 3
months of therapy and provides a strong rationale for
the continuation of the present study and for designing
larger randomised trials focusing on the response to
such a therapy of both neurological and cardiological
symptoms. Such investigations will confirm whether an
early diagnosis of FA can be exploited to initiate anti-
oxidant treatment and prevent the progression of this
disorder.
This work was supported by the Friedreich’s Ataxia Group (United
Kingdom), the National Lottery Charities Board, the Medical Research Council, the British Heart Foundation, and the Royal Free
Hampstead NHS Trust, which received a proportion of its funding
from the NHS Executive (the views expressed in this publication are
those of the authors and not necessarily those of the Trust or the
NHS Executive). At the time when the work was carried out, R. L.
was a Junior Research Fellow at Wolfson College, Oxford, United
Kingdom, and was supported by an EEC grant in the framework of
the BIOMED programme (contract BMH4CT965017).
We thank Pharma Nord for the supply of the CoQ10 and Vit E.
We are indebted to all the patients and their families for participating in the study.
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