It has recently been shown that the human pathology of Friedreich ataxia, the most common form of autosomal recessive spino-cerebellar ataxia which is often.
Coenzyme Q10 and vitamin E treatment of patients with Friedreich Ataxia. A 4 year clinical and 31P-MRS follow up study R. Lodi1, B. Rajagopalan2, A. H. Schapira3, P. E. Hart3, J. G. Crilley2, J. L. Bradley3, A. M. Blamire2, D. Manners2, P. Styles2, M. J. Cooper3 1
Dipartimento di Medicina Clinica e Biotecnologia Applicata, University of Bologna, Bologna, Italy, Italy, 2MRC Biochemical and Clinical Magnetic Resonance Unit, Department of Biochemistry, Oxford University, Oxford, UK, United Kingdom, 3University Department of Clinical Neurosciences, Royal Free Hospital, London, UK, United Kingdom Synopsis It has recently been shown that the human pathology of Friedreich ataxia, the most common form of autosomal recessive spino-cerebellar ataxia which is often associated with a cardiomyopathy, is characterised by mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo deficit of tissue energy metabolism. We present here neurological, echocardiographic and 31P-MRS 4 year follow up findings in ten patients that underwent antioxidant therapy. Antioxidant therapy resulted in a sustained improvement in cardiac and skeletal muscle bioenergetics in FA patients associated with lack of progression of both neurological and echocardiographic signs. Introduction Friedreich ataxia (FA) is the most common form of autosomal recessive spino-cerebellar ataxia and is often associated with a cardiomyopathy (1). FA is caused in the vast majority of cases by a GAA triplet expansion in the FA gene on chromosome 9q13. The FA gene product, frataxin, is a widely expressed mitochondrial protein which is severely reduced in FA patients. Loss of the homologue of frataxin in yeast is associated with mitochondrial iron overload, increased sensitivity to oxidative stress and profound deficit of oxidative phosphorylation (2). It has recently been demonstrated that the human pathology of FA is also characterised by mitochondrial iron accumulation, deficit of respiratory chain complex activities and in vivo deficit of tissue energy metabolism (3-5). It has been previously shown, using 31P-MRS, that the bioenergetic deficit in cardiac and skeletal muscle of FA patients was partially reversed after only 3 months of antioxidant therapy (Coenzyme Q10, 400 mg/day, and Vitamin E, 2100 IU/day) (6). We present here neurological, echocardiographic and 31P-MRS 4 year follow up findings from the same patient population. Methods Ten FA patients (5 males; age range 16-40 years; 28 ± 6 years, mean ± SD) and 10 healthy volunteers (5 males, age range 22-41; 28 ± 5, mean ± SD) were studied in a 2T Oxford magnet interfaced to a Bruker Avance spectrometer at baseline and after 6, 12, 24, 36 and 48 months of CoQ10 and Vit E oral administration. At the same time points FA patients were assessed neurologically, using the ICARS scale (6), and with echocardiography. Skeletal muscle 31P-MRS spectra were obtained from the right calf muscle at rest, during an aerobic incremental exercise of plantar flexion and the following recovery period (4). Relative metabolite concentrations were obtained by a time-domain fitting program (VARPRO/MRUI) and were corrected for magnetic saturation. The maximum rate of mitochondrial ATP synthesis (Vmax) was calculated from the initial rate of PCr post-exercise re-synthesis (V=k. ∆[PCr]) and the end-exercise [ADP] ([ADP]end): Vmax = V{1+(Km/[ADP]end)} (4). Cardiac 31P spectra were acquired using a 7 cm circular surface coil placed below the chest. Data were acquired using slice selective 1D-CSI (TR = heart rate) (7). Spectroscopic imaging rows corresponding to the heart were identified from the MR images and extracted from the data set. Data were analysed using a purpose written interactive frequency domain fitting program as described (6). PCr to ATP ratios were calculated including a correction for blood contamination and saturation (6). Data are presented as mean ± SD. Statistical analysis was performed by Student t test for paired and unpaired data, and p < 0.05 was taken to be significant. Figure 1. Cardiac PCr/ATP and calf muscle maximum rate of mitochondrial ATP production (Vmax) in FA patients at baseline (0) and after 6, 12, 24, 36 and 48 months of therapy. * p< 0.05 compared to values at baseline.
Cardiac muscle * * * * *
2.5 2
Months of therapy 0 6 12 24 36 48 Normal values
Calf muscle
75
50
PCr/ ATP 1.5
Vmax (mM/min) Controls
1
* * *
*
*
3
4
Table 1. Results of the neurological and echocardiographic evaluation of FA patients before (-) and after (+) 6, 12, 24, 36 and 48 months of Vit E and CoQ10. PWd, posterior wall thickness; IVSd, septal thickness.; FS, fractional shortening. * p< 0.05 compared to values at baseline (0).
25
FRDA patients
Vit E & CoQ10 + + + + +
ICARS (score) 50±12 53±13 54±12 51±10 48±12 48±16 0
PWd (cm) 1.10±0.24 1.09±0.21 1.11±0.30 1.17±0.27 1.14±0.17 1.10±0.24 < 1.10
IVSd (cm) 1.11±0.23 1.07±0.20 1.07±0.26 1.13±0.22 1.12±0.19 1.09±0.17 < 1.10
FS (%) 35±7 31±6 36±5 36±6 42±6* 41±6* > 25
0
0.5 0
1
2
3
4
0
Years of therapy
1
2
Years of therapy
Results Vit E and CoQ10 therapy resulted in a sustained improvement in cardiac and skeletal muscle bioenergetics in FA patients (Figure 1). After 48 months of therapy the mean cardiac PCr/ATP in FA patients had increased by 64%, (p=0.001) and skeletal muscle Vmax had risen by 44% (p=0.02). No deterioration of neurological and LVH after 48 months of follow up was detected. (Table 1). From the third year of treatment FS had significantly increased in the patients (Table 1). Discussion Oral CoQ10 and Vit E administration results in a sustained improvement in cellular bioenergetics in FA, as measured directly and in vivo in cardiac and skeletal muscle. In our FA patients partial reversal of energy metabolism deficit was associated with lack of progression of both neurological and echocardiographic signs. Our present findings provide a strong rationale for designing larger randomised trials focusing on the clinical response to such a therapy. References 1. Durr A. et al., N. Engl. J. Med., 335, 1169, 1996. 3. Bradley J. et al., Hum. Mol. Genet., 9, 275, 2000. 5. Lodi R. et al., Cardiovasc. Res., 52, 111, 2001 7. Blamire A.M. et al., Magn. Reson. Med., 41, 198, 1999.
Proc. Intl. Soc. Mag. Reson. Med. 11 (2003)
2. Babcock M. et al., Science, 276, 1709, 1997. 4. Lodi, R. et al., Proc. Natl. Acad. Sci. (U S A), 96, 11492, 1999. 6. Lodi R. et al., Ann. Neurol., 49, 590, 2001.
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